Carboxylic acid substituted heterocycles, derivatives thereof and methods of use

ABSTRACT

Selected novel carboxylic acid substituted heterocycle compounds are effective for prophylaxis and treatment of inflammation, tissue degradation, cancer, fibrosis and related diseases. The invention encompasses novel compounds, analogs, prodrugs and pharmaceutically acceptable salts thereof, pharmaceutical compositions and methods for prophylaxis and treatment of inflamation, tissue degradation and related diseases. The subject invention also relates to processes for making such compounds as well as to intermediates useful in such processes.

This application is a divisional of application of Ser. No. 09/588,978filed Jun. 7, 2000 which is a divisional of application Ser. No.09/213,031 filed Dec. 16, 1998, which claims the benefit of ProvisionalApplication Ser. No. 60/068,200, Filed Dec. 19, 1997, which are herebyincorporated by reference.

BACKGROUND OF THE INVENTION

The present invention relates to metalloproteinase inhibitors and, moreparticularly, relates to novel compounds, compositions and methods forprophylaxis and treatment of inflammation, tissue degradation and thelike. This invention, in particular, relates to novel carboxylic acidsubstituted heterocyclic compounds, compositions containing suchcompounds and methods of use of such compounds. The subject inventionalso relates to processes for making such compounds as well as tointermediates useful in such processes.

Metalloproteinase enzymes, such as collagenases, stromelysins andgelatinases, may contribute to the onset or etiology of, or exacerbatedisease states which are related to, connective tissue degradation andthe like. For example, matrix metalloproteinases, such as collagenases,stromelysins and gelatinases, are thought to be involved in the tissuebreakdown observed in rheumatoid arthritis; osteoarthritis; osteopenias(e.g., osteoporosis); periodontitis; gingivitis; corneal, epidermal andgastric ulceration; and tumour metastasis, invasion and growth; inneuroinflammatory disorders, such as myelin degradation (e.g., multiplesclerosis); and in angiogenesis dependent diseases, such as arthriticconditions; cancer; solid tumor growth; psoriasis; proliferativeretinopathies; neovascular glaucoma; ocular tumours; angiofibromas;hemangiomas; nephritis; pulmonary inflammation; and restenosis.

WO 96/33172 discloses N-arylsulfonyl and N-heteroarylsulfonylsubstituted 6 membered ring heterocycle hydroxamic acid derivatives,such as N-arylsulfonyl- andN-heteroarylsulfonyl-piperidinyl-2-hydroxamic acid compounds, and theirpreparation and use as inhibitors of matrix metalloproteinases and TNFproduction.

EP 606046 discloses N-arylsulfonyl and N-heteroarylsulfonyl substituted5-6 membered ring heterocycle hydroxamic acid derivatives, such asN-arylsulfonyl- and N-heteroarylsulfonyl-piperidinyl-2-hydroxamic acidcompounds and N-arylsulfonyl- andN-heteroarylsulfonyl-1,2,3,4-tetrahydroisoquinolinyl-2-hydroxamic acidcompounds, preparation and use as inhibitors of matrixmetalloproteinases.

WO 97/18194 discloses certain cyclic and heterocyclic N-substitutedα-substituted iminohydroxamic and carboxylic acids, and theirpreparation and use as inhibitors of matrix metalloproteinases.

EP 803505 discloses optionally substituted aryl fused N-heterocycles andtheir preparation and use as inhibitors of metalloproteinases.

BRIEF DESCRIPTION OF THE INVENTION

The present invention relates to selected metalloproteinase inhibitorycompounds, analogs and pharmaceutically acceptable salts and prodrugsthereof. The subject compounds are characterized as carboxylic acidsubstituted heterocyclic compounds. The compounds are useful in theprophylaxis and treatment of inflammation, tissue degradation andrelated diseases. Therefore, this invention also encompassespharmaceutical compositions and methods for prophylaxis and treatment ofinflamation, tissue degradation and related diseases. The subjectinvention also relates to processes for making such compounds, as wellas to intermediates useful in such processes.

DETAILED DESCRIPTION OF THE INVENTION

In accordance with the present invention, there is provided a compoundof the Formula I below:

or a pharmacutically acceptable salt thereof, wherein

m is 1 or 2; and n is 0, 1 or 2;

R¹ is (1) an alkyl, alkenyl, alkynyl, cycloalkyl or heterocyclyl radicaloptionally substituted by 1-3 radicals of —OH, —OR³, —SR³, —S(O)R³,—S(O)₂R³, —C(O)R³, —NR³R⁴, aryl, heteroaryl, cycloalkyl or heterocyclyl;or (2) an aryl radical optionally substituted by an optionallysubstituted monocyclic heteroaryl or heterocyclyl radical of 5-6 ringmembers which is optionally substituted by a phenyl radical ormonocyclic heteroaryl radical of 5-6 ring members; or (3) a heteroarylradical optionally substituted by an optionally substituted phenyl or amonocyclic heteroaryl or heterocyclyl radical of 5-6 ring members whichis optionally substituted by a phenyl radical or monocyclic heteroarylradical of 5-6 ring members; wherein the phenyl, aryl, heteroaryl,cycloalkyl and heterocyclyl radicals of (1), (2) and (3) are optionallysubstituted by 1-3 radicals of hydroxy, —OR³, —SR³, —S(O)R³, —S(O)₂R³,—C(O)R³, —NR³R⁴, amino, alkanoylamino, alkylsulfonylamino,alkoxycarbonylamino, alkoxycarbonyl, cyano, halo, azido, alkyl orhaloalkyl;

preferably, R¹ is (1) an C₁-C₁₂ alkyl, C₂-C₁₂ alkenyl, C₂-C₁₂ alkynyl,cycloalkyl or heterocyclyl radical optionally substituted by 1-3radicals of —OH, —OR³, —SR³, —S(O)R³, —S(O)₂R³, —C(O)R³, —NR³R⁴, aryl,heteroaryl, cycloalkyl or heterocyclyl; or ((2) an aryl radicaloptionally substituted by an optionally substituted monocyclicheteroaryl or heterocyclyl radical of 5-6 ring members which isoptionally substituted by a phenyl radical or monocyclic heteroarylradical of 5-6 ring members; or (3) a heteroaryl radical optionallysubstituted by an optionally substituted phenyl or a monocyclicheteroaryl or heterocyclyl radical of 5-6 ring members which isoptionally substituted by a phenyl radical or monocyclic heteroarylradical of 5-6 ring members; wherein the phenyl, aryl, heteroaryl,cycloalkyl and heterocyclyl radicals of (1), (2) and (3) are optionallysubstituted by 1-3 radicals of hydroxy, —OR³, —SR³, —S(O)R³, —S(O)₂R³,—C(O)R³, —NR³R⁴, amino, C₁-C₈ alkanoylamino, C₁-C₈ alkylsulfonylamino,C₁-C₈ alkoxycarbonylamino, C₁-C₈ alkoxycarbonyl, cyano, halo, azido,C₁-C₈ alkyl or C₁-C₈ haloalkyl of 1-3 halo radicals;

more preferably, R¹ is (1) a C₁-C₁₂ alkyl, C₂-C₁₂ alkenyl, C₂-C₁₂alkynyl, cycloalkyl or heterocyclyl radical optionally substituted by1-3 radicals of —OH, —OR³, —SR³, —S(O)R³, —S(O)₂R³, —C(O)R³, —NR³R⁴,aryl, heteroaryl, cycloalkyl or heterocyclyl; or (2) an aryl radicaloptionally substituted by an optionally substituted monocyclicheteroaryl or heterocyclyl radical of 5-6 ring members which isoptionally substituted by a phenyl radical or monocyclic heteroarylradical of 5-6 ring members; or (3) a heteroaryl radical optionallysubstituted by an optionally substituted phenyl or a monocyclicheteroaryl or heterocyclyl radical of 5-6 ring members which isoptionally substituted by a phenyl radical or monocyclic heteroarylradical of 5-6 ring members; wherein the phenyl, aryl, heteroaryl,cycloalkyl and heterocyclyl radicals of (1), (2) and (3) are optionallysubstituted by 1-3 radicals of hydroxy, —OR³, —SR³, —S(O)R³, —S(O)₂R³,—C(O)R³, —NR³R⁴, amino, C₁-C₄ alkanoylamino, C₁-C₄ alkylsulfonylamino,C₁-C₄ alkoxycarbonylamino, C₁-C₄ alkoxycarbonyl, cyano, halo, azido,C₁-C₆ alkyl or C₁-C₄ haloalkyl of 1-3 halo radicals;

more preferably, R¹ is (1) a C₁-C₁₂ alkyl radical optionally substitutedby 1-3 radicals of —OH, —OR³, —SR³, —S(O)R³, —S(O)₂R³, —C(O)R³, —NR³R⁴,aryl, heteroaryl, cycloalkyl or heterocyclyl; or (2) an aryl radicaloptionally substituted by an optionally substituted monocyclicheteroaryl or heterocyclyl radical of 5-6 ring members which isoptionally substituted by a phenyl radical or monocyclic heteroarylradical of 5-6 ring members; or (3) a heteroaryl radical optionallysubstituted by an optionally substituted phenyl or a monocyclicheteroaryl or heterocyclyl radical of 5-6 ring members which isoptionally substituted by a phenyl radical or monocyclic heteroarylradical of 5-6 ring members; wherein the phenyl, aryl, heteroaryl,cycloalkyl and heterocyclyl radicals of (1), (2) and (3) are optionallysubstituted by 1-3 radicals of hydroxy, —OR³, —SR³, —S(O)R³, —S(O)₂R³,—C(O)R³, —NR³R⁴, amino, acetylamino, methylsulfonylamino, C₁-C₄alkoxycarbonylamino, C₁-C₄ alkoxycarbonyl, cyano, halo, C₁-C₆ alkyl or—CF₃ radicals;

more preferably, R¹ is (1) an C₁-C₁₂ alkyl radical optionallysubstituted by 1-3 radicals of —OH, —OR³, —SR³, —S(O)₂R³, —NR³R⁴, aryl,heteroaryl, cycloalkyl or heterocyclyl; or (2) an aryl radicaloptionally substituted by an optionally substituted monocyclicheteroaryl or heterocyclyl radical of 5-6 ring members which isoptionally substituted by a phenyl radical or monocyclic heteroarylradical of 5-6 ring members; or (3) a heteroaryl radical optionallysubstituted by an optionally substituted phenyl or a monocyclicheteroaryl or heterocyclyl radical of 5-6 ring members which isoptionally substituted by a phenyl radical or monocyclic heteroarylradical of 5-6 ring members; wherein the phenyl, aryl, heteroaryl,cycloalkyl and heterocyclyl radicals of (1), (2) and (3) are optionallysubstituted by 1-3 radicals of hydroxy, —OR³, —SR³, —S(O)₂R³, —NR³R⁴,amino, acetylamino, methylsulfonylamino, C₁-C₄ alkoxycarbonylamino,C₁-C₄ alkoxycarbonyl, cyano, halo, C₁-C₆ alkyl or —CF₃ radicals;

more preferably, R¹ is (1) an C₁-C₄ alkyl radical substituted by 1-2radicals of —OH, —OR³, —NR³R⁴, aryl or heteroaryl; or (2) an arylradical optionally substituted by a monocyclic heteroaryl radical of 5-6ring members; or (3) a heteroaryl radical optionally substituted by aphenyl radical; wherein the phenyl, aryl and heteroaryl radicals of (1),(2) and (3) are optionally substituted by 1-2 radicals of hydroxy, —OR³,—SR³, —S(O)₂R³, —NR³R⁴, amino, acetylamino, methylsulfonylamino, C₁-C₄alkoxycarbonylamino, C₁-C₄ alkoxycarbonyl, halo, C₁-C₆ alkyl or —CF₃radicals;

more preferably, R¹ is aryl or heteroaryl radicals optionallysubstituted by 1-2 radicals of hydroxy, —OR³, —SR³, —S(O)₂R³, —NR³R⁴,amino, acetylamino, methylsulfonylamino, C₁-C₄ alkoxycarbonylamino,C₁-C₄ alkoxycarbonyl, halo, C₁-C₆ alkyl or —CF₃ radicals; and

more preferably, R¹ is an aryl radical optionally substituted by 1-2radicals of hydroxy, —OR³, —S(O)₂R³, —NR³R⁴, amino, acetylamino,methylsulfonylamino, halo, C₁-C₄ alkyl or —CF₃ radicals;

more preferably, R¹ is a phenyl or biphenyl radical optionallysubstituted by 1-2 radicals of hydroxy, —OR³, —S(O)₂R³, —NR³R⁴, amino,acetylamino, methylsulfonylamino, halo, C₁-C₄ alkyl or —CF₃ radicals;

most preferably, R¹ is a phenyl or biphenyl radical optionallysubstituted by 1-2 radicals of hydroxy, —OR³, halo, methyl or —CF₃radicals; and

provided that the total number of phenyl, aryl, heteroaryl, cycloalkyland heterocyclyl radicals in R¹ is preferably 0-3, more preferably, 0-2,most preferably, 1-2;

wherein each R³ is independently an alkyl, haloalkyl, aryl, heteroaryl,aryl-alkyl or heteroaryl-alkyl radical, wherein the aryl and heteroarylradicals are optionally substituted by 1-3 radicals of hydroxy, alkoxy,alkylthiol, amino, alkanoylamino, alkylsulfonylamino, alkylsulfinyl,alkylsulfonyl, alkoxycarbonylamino, alkoxycarbonyl, cyano, halo, azido,alkyl, haloalkyl or haloalkoxy;

preferably, each R³ is independently a C₁-C₈ alkyl, C₁-C₈ haloalkyl of1-3 halo radicals, aryl, heteroaryl, aryl-C₁-C₄-alkyl orheteroaryl-C₁-C₄-alkyl radical, wherein the aryl and heteroaryl radicalsare optionally substituted by 1-3 radicals of hydroxy, C₁-C₄ alkoxy,C₁-C₄ alkylthiol, amino, C₁-C₈ alkanoylamino, C₁-C₈ alkylsulfonylamino,C₁-C₄ alkylsulfinyl, C₁-C₄ alkylsulfonyl, C₁-C₈ alkoxycarbonylamino,C₁-C₈ alkoxycarbonyl, cyano, halo, azido, C₁-C₈ alkyl, C₁-C₈ haloalkylof 1-3 halo radicals or C₁-C₈ haloalkoxy of 1-3 halo radicals;

more preferably, each R³ is independently a C₁-C₄ alkyl, C₁-C₄ haloalkylof 1-3 halo radicals, aryl, heteroaryl, aryl-C₁-C₄-alkyl orheteroaryl-C₁-C₄-alkyl radical, wherein the aryl and heteroaryl radicalsare optionally substituted by 1-3 radicals of hydroxy, C₁-C₄ alkoxy,C₁-C₄ alkylthiol, amino, C₁-C₄ alkanoylamino, C₁-C₄ alkylsulfonylamino,C₁-C₄ alkylsulfinyl, C₁-C₄ alkylsulfonyl, C₁-C₄ alkoxycarbonylamino,C₁-C₄ alkoxycarbonyl, cyano, halo, azido, C₁-C₄ alkyl, C₁-C₄ haloalkylof 1-3 halo radicals or C₁-C₄ haloalkoxy of 1-3 halo radicals;

more preferably, each R³ is independently an C₁-C₄ alkyl, —CF₃, aryl,heteroaryl, aryl-C₁-C₄-alkyl or heteroaryl-C₁-C₄-alkyl radical, whereinthe aryl and heteroaryl radicals are optionally substituted by 1-3radicals of hydroxy, C₁-C₄ alkoxy, C₁-C₄ alkylthiol, amino, acetylamino,methylsulfonylamino, C₁-C₄ alkylsulfonyl, C₁-C₄ alkoxycarbonylamino,C₁-C₄ alkoxycarbonyl, cyano, halo, C₁-C₄ alkyl, —CF₃ or —OCF₃;

more preferably, each R³ is independently a C₁-C₄ alkyl, —CF₃, aryl,heteroaryl, aryl-C₁-C₂-alkyl or heteroaryl-C₁-C₂-alkyl radical, whereinthe aryl and heteroaryl radicals are optionally substituted by 1-2radicals of hydroxy, C₁-C₄ alkoxy, C₁-C₄ alkylthiol, amino, acetylamino,methylsulfonylamino, C₁-C₄ alkylsulfonyl, C₁-C₄ alkoxycarbonylamino,C₁-C₄ alkoxycarbonyl, cyano, halo, C₁-C₄ alkyl, —CF₃ or —OCF₃;

more preferably, each R³ is independently a C₁-C₄ alkyl, —CF₃, aryl,heteroaryl, aryl-C₁-C₂-alkyl or heteroaryl-C₁-C₂-alkyl radical, whereinthe aryl and heteroaryl radicals are optionally substituted by 1-2radicals of hydroxy, C₁-C₂ alkoxy, C₁-C₂ alkylthiol, amino, acetylamino,methylsulfonylamino, C₁-C₂ alkylsulfonyl, C₁-C₄ alkoxycarbonylamino,C₁-C₄ alkoxycarbonyl, halo, C₁-C₂ alkyl, —CF₃ or —OCF₃;

more preferably, each R³ is independently a C₁-C₄ alkyl, —CF₃, aryl,heteroaryl, arylmethyl or heteroarylmethyl radical;

more preferably, each R³ is independently an C₁-C₄ alkyl, —CF₃, phenyl,heteroaryl, phenylmethyl or heteroarylmethyl radical;

most preferably, each R³ is independently an methyl, —CF₃, phenyl,heteroaryl, phenylmethyl or heteroarylmethyl radical; and

each R⁴ is independently a hydrogen or alkyl radical; preferably, eachR⁴ is independently a hydrogen or C₁-C₈ alkyl radical; more preferably,each R⁴ is independently a hydrogen or C₁-C₄ alkyl radical; mostpreferably, each R⁴ is independently a hydrogen or methyl radical; and

R¹¹ is a —C(O)—R³¹, —C(O)—OR³⁰, —C(O)—NR³²R³¹, —S(O)₂—R³⁰ or—S(O)₂—NR³²R³¹ radical; preferably, R¹¹ is a —C(O)—R³¹ or —S(O)₂—R³⁰ or—S(O)₂—NR³²R³¹ radical;

wherein R⁵ and R⁶ are each independently a hydrogen or alkyl radical;preferably, R⁵ and R⁶ are each independently a hydrogen or C₁-C₄ alkylradical; and more preferably, R⁵ and R⁶ are each a hydrogen radical; orCR⁵-CR⁶ is C═C (double bonded carbon atoms);

wherein R⁹ and R¹⁰ are each independently —B-A, provided that thecombined total number of aryl, heteroaryl, cycloalkyl and heterocyclylradicals in R⁹, R¹⁰ and R¹¹ is 0-3, preferably, 0-2;

wherein each B is independently a (1) bond; (2) alkyl, alkenyl oralkynyl radical optionally substituted by (a) 1-3 radicals of amino,alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino,alkylsulfonylamino, hydroxy, alkoxy, alkylthio, cyano or halo, and/or(b) 1-2 radicals of heterocyclyl, aryl or heteroaryl optionallysubstituted by 1-3 radicals of amino, alkylamino, dialkylamino,alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy,alkylthio, cyano, halo, alkyl, haloalkyl or haloalkoxy; (3) heterocyclylradical optionally substituted by 1-3 radicals of amino, alkylamino,dialkylamino, alkanoylamino, alkoxycarbonyl amino, alkylsulfonylamino,hydroxy, alkoxy, alkylthio, cyano, alkyl, haloalkyl or haloalkoxy; or(4) aryl or heteroaryl radical optionally substituted by 1-3 radicals ofamino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino,alkylsulfonylamino, hydroxy, alkoxy, alkylthio, cyano, halo, alkyl,haloalkyl or haloalkoxy;

preferably, each B is independently a (1) bond; (2) C₁-C₈ alkyl, C₂-C₈alkenyl or C₂-C₈ alkynyl radical optionally substituted by (a) 1-3radicals of amino, C₁-C₄ alkylamino, di-(C₁-C₄ alkyl)amino, C₁-C₅alkanoylamino, (C₁-C₄ alkoxy)carbonylamino, C₁-C₄ alkylsulfonylamino,hydroxy, C₁-C₄ alkoxy, C₁-C₄ alkylthio, cyano or halo, and/or (b) 1-2radicals of heterocyclyl, aryl or heteroaryl optionally substituted by1-3 radicals of amino, C₁-C₄ alkylamino, di-(C₁-C₄ alkyl)amino, C₁-C₅alkanoylamino, (C₁-C₄ alkoxy)carbonylamino, C₁-C₄ alkyl sulfonylamino,hydroxy, C₁-C₄ alkoxy, C₁-C₄ alkylthio, cyano, halo, C₁-C₄ alkyl, C₁-C₄haloalkyl of 1-3 halo radicals or C₁-C₄ haloalkoxy of 1-3 halo radicals;(3) heterocyclyl radical optionally substituted by 1-3 radicals ofamino, C₁-C₄ alkylamino, di-(C₁-C₄ alkyl) amino, C₁-C₅ alkanoylamino,(C₁-C₄ alkoxy)carbonylamino, C₁-C₄ alkylsulfonylamino, hydroxy, C₁-C₄alkoxy, C₁-C₄ alkylthio, cyano, C₁-C₄ alkyl, C₁-C₄ haloalkyl of 1-3 haloradicals or C₁-C₄ haloalkoxy of 1-3 halo radicals; or (4) aryl orheteroaryl radical optionally substituted by 1-3 radicals of amino,C₁-C₄ alkylamino, di-(C₁-C₄ alkyl)-amino, C₁-C₅ alkanoylamino, (C₁-C₄alkoxy)carbonylamino, C₁-C₄ alkylsulfonylamino, hydroxy, C₁-C₄ alkoxy,C₁-C₄ alkylthio, cyano, halo, C₁-C₄ alkyl, C₁-C₈ haloalkyl of 1-3 haloradicals or C₁-C₈ haloalkoxy of 1-3 halo radicals;

more preferably, each B is independently a (1) bond; (2) C₁-C₈ alkylradical optionally substituted by (a) a radical of amino, C₁-C₄alkylamino, di-(C₁-C₄ alkyl)-amino, C₁-C₅ alkanoylamino, (C₁-C₄alkoxy)carbonylamino, C₁-C₄ alkylsulfonylamino, hydroxy, C₁-C₄ alkoxy,C₁-C₄ alkylthio, cyano, and/or (b) 1-3 halo radicals, and/or (c) 1-2radicals of heterocyclyl, aryl or heteroaryl optionally substituted by1-3 radicals of amino, C₁-C₄ alkylamino, di-(C₁-C₄ alkyl)amino, C₁-C₅alkanoylamino, (C₁-C₄ alkoxy)carbonylamino, C₁-C₄ alkylsulfonylamino,hydroxy, C₁-C₄ alkoxy, C₁-C₄ alkylthio, cyano, halo, C₁-C₄ alkyl, C₁-C₄haloalkyl of 1-3 halo radicals or C₁-C₄ halo alkoxy of 1-3 haloradicals; (3) heterocyclyl radical; or (4) aryl or heteroaryl radicaloptionally substituted by 1-3 radicals of amino, C₁-C₄ alkylamino,di-(C₁-C₄ alkyl) amino, C₁-C₅ alkanoylamino, (C₁-C₄alkoxy)carbonylamino, C₁-C₄ alkylsulfonylamino, hydroxy, C₁-C₄ alkoxy,C₁-C₄ alkylthio, cyano, halo, C₁-C₄ alkyl, C₁-C₄ haloalkyl of 1-3 haloradicals or C₁-C₄ haloalkoxy of 1-3 halo radicals;

more preferably, each B is independently a (1) bond; (2) C₁-C₈ alkylradical optionally substituted by (a) a radical of amino, C₁-C₄alkylamino, di-(C₁-C₄ alkyl)-amino, C₁-C₅ alkanoylamino, (C₁-C₄alkoxy)carbonylamino, C₁-C₄ alkylsulfonylamino, hydroxy, C₁-C₄ alkoxy,C₁-C₄ alkyl thio, cyano, and/or (b) 1-3 halo radicals, and/or (c) 1-2radicals of heterocyclyl, aryl or heteroaryl optionally substituted by1-3 radicals of amino, C₁-C₄ alkylamino, di-(C₁-C₄ alkyl)amino, C₁-C₅alkanoylamino, (C₁-C₄ alkoxy) carbonylamino, C₁-C₄ alkylsulfonylamino,hydroxy, C₁-C₄ alkoxy, C₁-C₄ alkylthio, cyano, halo, C₁-C₄ alkyl, —CF₃or —OCF₃ radicals; (3) heterocyclyl radical; or (4) aryl or heteroarylradical optionally substituted by 1-3 radicals of amino, C₁-C₄alkylamino, di-(C₁-C₄ alkyl)amino, C₁-C₅ alkanoylamino, (C₁-C₄alkoxy)carbonylamino, C₁-C₄ alkyl sulfonylamino, hydroxy, C₁-C₄ alkoxy,C₁-C₄ alkylthio, cyano, halo, C₁-C₄ alkyl, —CF₃ or —OCF₃ radicals;

more preferably, each B is independently a (1) bond; (2) C₁-C₄ alkylradical optionally substituted by (a) a radical of amino, C₁-C₂alkylamino, di-(C₁-C₂ alkyl)-amino, C₁-C₂ alkanoylamino, (C₁-C₄alkoxy)carbonylamino, hydroxy, C₁-C₂ alkoxy, and/or (b) 1-2 haloradicals, and/or (c) a radical of heterocyclyl, aryl or heteroaryloptionally substituted by 1-2 radicals of amino, C₁-C₂ alkylamino,di-(C₁-C₂ alkyl)amino, C₁-C₂ alkanoylamino, (C₁-C₄ alkoxy)carbonylamino,C₁-C₂ alkylsulfonylamino, hydroxy, C₁-C₂ alkoxy, C₁-C₂ alkylthio, halo,C₁-C₄ alkyl, —CF₃ or —OCF₃ radicals; (3) heterocyclyl radical; or (4)aryl or heteroaryl radical optionally substituted by 1-2 radicals ofamino, C₁-C₂ alkylamino, di-(C₁-C₂ alkyl)amino, C₁-C₂ alkanoylamino,(C₁-C₄ alkoxy) carbonylamino, C₁-C₂ alkylsulfonylamino, hydroxy, C₁-C₂alkoxy, C₁-C₂ alkylthio, halo, C₁-C₄ alkyl, —CF₃ or —OCF₃ radicals;

more preferably, each B is independently a (1) bond or C₁-C₄ alkylradical; or (2) aryl or heteroaryl radical optionally substituted by aradical of amino, C₁-C₂ alkylamino, di-(C₁-C₂ alkyl)amino, C₁-C₂alkanoylamino, (C₁-C₄ alkoxy)carbonylamino, C₁-C₂ alkylsulfonylamino,hydroxy, C₁-C₂ alkoxy, C₁-C₂ alkylthio, halo, C₁-C₄ alkyl, —CF₃ or —OCF₃radicals; and

most preferably, each B is independently a bond, C₁-C₄ alkyl, aryl orheteroaryl radical;

wherein each A is independently a (1) hydrogen radical; (2) halo, cyanoor nitro radical; (3) —C(O)—R³⁰, —C(O)—OR³¹, —C(O)—NR³²R³¹ or—C(NR³²)R³¹ radical; (4) —OR³¹, —O—C(O)—R³¹, —O—C(O)—NR³²R³¹ or—O—C(O)—NR³³—S(O)₂—R³⁰ radical; (5) —SR³¹, —S(O)—R³⁰, —S(O)₂—R³⁰,—S(O)₂—NR³²R³¹, —S(O)₂—NR³³—C(O)—R³¹, —S(O)₂—NR³³—C(O)—OR³⁰ or—S(O)₂—NR³³—C(O)—NR³²R³¹ radical; or (6) —NR³²R³¹, —NR³³—C(O)—R³¹,—NR³³—C(O)—OR³⁰, —NR³³—C(O)—NR³²R³¹, —NR³³—C(NR³²)—NR³²R³¹,—NR³³—S(O)₂—R³⁰ or —NR³³—S(O)₂—NR³²R³¹ radical;

preferably, each A is independently a (1) hydrogen radical; (2) halo,cyano or nitro radical; (3) —C(O)—R³⁰, —C(O)—OR³¹, —C(O)—NR³²R³¹ or—C(NR³²)—NR³²R³¹ radical; (4) —OR³¹, —O—C(O)—R³¹, —O—C(O)—NR³²R³¹ or—O—C(O)—NR³³—S(O)₂—R³⁰ radical; (5) —SR³¹, —S(O)—R³⁰, —S(O)₂—R³⁰,—S(O)₂—NR³²R³¹, —S(O)₂—NR³³—C(O)—R³¹, —S(O)₂—NR³³—C(O)—OR³⁰ or—S(O)₂—NR³³—C(O)—NR³²R³¹ radical; or (6) —NR³²R³¹, —NR³³—C(O)—R³¹,—NR³³—C(O)—OR³⁰, —NR³³—C(O)—NR³²R³¹, —NR³³—C(NR³²)—NR³²R³¹,—NR³³—S(O)₂—R³⁰ or —NR³³—S(O)₂—NR³²R³¹ radical;

more preferably, each A is independently a hydrogen, halo, cyano, nitro,—C(O)—R³⁰, —C(O)—OR³¹, —C(O)—NR³²R³¹, —C(NR³²)—NR³²R³¹, —OR³¹,—O—C(O)—R³¹, —O—C(O)—NR³²R³¹, —SR³¹, —S(O)—R³⁰, S(O)₂—R³⁰,—S(O)₂—NR³²R³¹, —NR³²R³¹, —NR³³—C(O)—R³¹, —NR³³—C(O)—OR³⁰,—NR³³—C(O)—NR³²R³¹, —NR³³—C(NR³²)—NR³²R³¹, —NR³³—S(O)₂—R³⁰ or—NR³³—S(O)₂—NR³²R³¹ radical;

more preferably, each A is independently a hydrogen, halo, —C(O)—R³⁰,—C(O)—OR³¹, —C(O)—NR³²R³¹, —C(NR³²)—NR³²R³¹, —OR³¹, —SR³¹, —S(O)₂—R³⁰,—S(O)₂—NR³²R³¹, —NR³²R³¹, —NR³³—C(O)—R³¹, —NR³³—C(O)—OR³⁰,—NR³³—C(O)—NR³²R³¹, —NR³³—S(O)₂—R³⁰ or —NR³³—S(O)₂—NR³²R³¹ radical;

more preferably, each A is independently a hydrogen, halo, —C(O)—R³⁰,—C(O)—NR³²R³¹, —C(NR³²)—NR³²R³¹, —OR³¹, —SR³¹, —S(O)₂—R³⁰,—S(O)₂—NR³²R³¹, —NR³²R³¹, —NR³³—C(O)—R³¹ or —NR³³—S(O)₂—R³⁰ radical; andmost preferably, each A is independently a hydrogen, halo, —C(O)—R³⁰ or—C(O)—NR³²R³¹ radical;

wherein each R is independently (1) alkyl, alkenyl or alkynyl radicaloptionally substituted by 1-3 radicals of —CO₂R³⁴, amino, alkylamino,dialkylamino, alkanoylamino, alkoxycarbonylamino,N-(alkoxycarbonyl)-N-(alkyl)amino, aminocarbonylamino,alkylsulfonylamino, hydroxy, alkoxy, alkylthio, alkylsulfinyl,alkylsulfonyl, cyano, halo or aralkoxy, arylalkylthio,arylalkylsulfonyl, cycloalkyl, heterocyclyl, aryl or heteroarylradicals, wherein the cycloalkyl, heterocyclyl, aryl and heteroarylradicals are optionally substituted by 1-3 radicals of amino,alkylamino, dialkylamino, alkanoylamino, alkoxycarbonyl amino,alkylsulfonylamino, alkanoyl, alkoxycarbonyl, hydroxy, alkoxy,alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, halo, alkyl, haloalkylor haloalkoxy; (2) heterocyclyl radical optionally substituted by 1-3radicals of amino, alkylamino, dialkylamino, alkanoylamino,alkoxycarbonylamino, alkylsulfonylamino, alkoxycarbonyl, hydroxy,alkoxy, alkylthio, cyano, alkyl, haloalkyl or haloalkoxy; or (3) aryl orheteroaryl radical optionally substituted by 1-3 radicals of amino,alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino,alkylsulfonylamino, alkoxycarbonyl, hydroxy, alkoxy, alkylthio, cyano,halo, azido, alkyl, haloalkyl or haloalkoxy;

preferably, each R³⁰ is independently (1) C₁-C₈ alkyl, C₂-C₈ alkenyl orC₂-C₈ alkynyl radical optionally substituted by 1-3 radicals of —CO₂R³⁴,amino, C₁-C₄ alkylamino, di-(C₁-C₄ alkyl)amino, C₁-C₅ alkanoylamino,(C₁-C₄ alkoxy)carbonylamino, N-((C₁-C₄ alkoxy)carbonyl)-N-(C₁-C₄alkyl)amino, aminocarbonylamino, C₁-C₄ alkylsulfonylamino, hydroxy,C₁-C₄ alkoxy, C₁-C₄ alkylthio, C₁-C₄ alkylsulfinyl, C₁-C₄ alkylsulfonyl,cyano, halo, aryl-C₁-C₄-alkoxy, aryl-C₁-C₄-alkylthio,aryl-C₁-C₄-alkylsulfonyl, C₃-C₈ cycloalkyl, heterocyclyl, aryl orheteroaryl radicals, wherein the cycloalkyl, heterocyclyl, aryl andheteroaryl radicals are optionally substituted by 1-3 radicals of amino,C₁-C₄ alkylamino, di-(C₁-C₄ alkyl) amino, C₁-C₅ alkanoylamino, (C₁-C₄alkoxy)carbonylamino, C₁-C₄ alkylsulfonylamino, C₁-C₅ alkanoyl, (C₁-C₄alkoxy) carbonyl, hydroxy, C₁-C₄ alkoxy, C₁-C₄ alkylthio, C₁-C₄alkylsulfinyl, C₁-C₄ alkylsulfonyl, cyano, halo, C₁-C₄ alkyl, C₁-C₄haloalkyl of 1-3 halo radicals or C₁-C₄ haloalkoxy of 1-3 halo radicals;(2) heterocyclyl radical optionally substituted by 1-3 radicals ofamino, C₁-C₄ alkylamino, di-(C₁-C₄ alkyl)amino, C₁-C₅ alkanoylamino,(C₁-C₄ alkoxy)carbonylamino, C₁-C₄ alkylsulfonylamino, (C₁-C₄alkoxy)carbonyl, hydroxy, C₁-C₄ alkoxy, C₁-C₄ alkylthio, cyano, C₁-C₄alkyl, C₁-C₄ haloalkyl of 1-3 halo radicals or C₁-C₄ haloalkoxy of 1-3halo radicals; or (3) aryl or heteroaryl radical optionally substitutedby 1-3 radicals of amino, C₁-C₄ alkylamino, di-(C₁-C₄ alkyl)amino, C₁-C₅alkanoylamino, (C₁-C₄ alkoxy) carbonylamino, C₁-C₄ alkylsulfonylamino,(C₁-C₄ alkoxy)carbonyl, hydroxy, C₁-C₄ alkoxy, C₁-C₄ alkylthio, cyano,halo, azido, C₁-C₄ alkyl, C₁-C₄ haloalkyl of 1-3 halo radicals or C₁-C₄haloalkoxy of 1-3 halo radicals;

more preferably, each R³⁰ is independently (1) C₁-C₆ alkyl radicaloptionally substituted by 1-3 radicals of —CO₂R³⁴, amino, C₁-C₄alkylamino, di-(C₁-C₄ alkyl)amino, C₁-C₅ alkanoylamino, (C₁-C₄alkoxy)carbonylamino, N-((C₁-C₄ alkoxy)carbonyl)-N-(C₁-C₄ alkyl)amino,aminocarbonylamino, C₁-C₄ alkylsulfonylamino, hydroxy, C₁-C₄ alkoxy,C₁-C₄ alkylthio, C₁-C₄ alkylsulfinyl, C₁-C₄ alkylsulfonyl, cyano, halo,aryl-C₁-C₄-alkoxy, aryl-C₁-C₄-alkylthio, aryl-C₁-C₄-alkylsulfonyl, C₃-C₈cycloalkyl, heterocyclyl, aryl or heteroaryl radicals, wherein thecycloalkyl, heterocyclyl, aryl and heteroaryl radicals are optionallysubstituted by 1-3 radicals of amino, C₁-C₄ alkylamino, di-(C₁-C₄alkyl)amino, C₁-C₅ alkanoylamino, (C₁-C₄ alkoxy)carbonylamino, C₁-C₄alkylsulfonylamino, C₁-C₅ alkanoyl, (C₁-C₄ alkoxy)carbonyl, hydroxy,C₁-C₄ alkoxy, C₁-C₄ alkylthio, C₁-C₄ alkylsulfinyl, C₁-C₄ alkylsulfonyl,cyano, halo, C₁-C₄ alkyl, C₁-C₄ haloalkyl of 1-3 halo radicals or C₁-C₄haloalkoxy of 1-3 halo radicals; (2) heterocyclyl radical optionallysubstituted by 1-3 radicals of amino, C₁-C₄ alkylamino, di-(C₁-C₄ alkyl)amino, C₁-C₅ alkanoylamino, (C₁-C₄ alkoxy)carbonylamino, C₁-C₄alkylsulfonylamino, (C₁-C₄ alkoxy)carbonyl, hydroxy, C₁-C₄ alkoxy, C₁-C₄alkylthio, cyano, C₁-C₄ alkyl, C₁-C₄ haloalkyl of 1-3 halo radicals orC₁-C₄ haloalkoxy of 1-3 halo radicals; or (3) aryl or heteroaryl radicaloptionally substituted by 1-3 radicals of amino, C₁-C₄ alkylamino,di-(C₁-C₄ alkyl)amino, C₁-C₅ alkanoylamino, (C₁-C₄ alkoxy)carbonylamino,C₁-C₄ alkylsulfonylamino, (C₁-C₄ alkoxy)carbonyl, hydroxy, C₁-C₄ alkoxy,C₁-C₄ alkylthio, cyano, halo, azido, C₁-C₄ alkyl, C₁-C₄ haloalkyl of 1-3halo radicals or C₁-C₄ haloalkoxy of 1-3 halo radicals;

more preferably, each R³⁰ is independently (1) C₁-C₆ alkyl radicaloptionally substituted by 1-3 radicals of —CO₂R³⁴, amino, C₁-C₄alkylamino, di-(C₁-C₄ alkyl)amino, C₁-C₅ alkanoylamino, (C₁-C₄alkoxy)carbonylamino, N-((C₁-C₄ alkoxy)carbonyl)-N-(C₁-C₄ alkyl)amino,aminocarbonylamino, C₁-C₄ alkylsulfonylamino, hydroxy, C₁-C₄ alkoxy,C₁-C₄ alkylthio, C₁-C₄ alkylsulfinyl, C₁-C₄ alkylsulfonyl, cyano, halo,aryl-C₁-C₄-alkoxy, aryl-C₁-C₄-alkylthio, aryl-C₁-C₄-alkylsulfonyl, C₃-C₈cycloalkyl, heterocyclyl, aryl or heteroaryl radicals, wherein thecycloalkyl, heterocyclyl, aryl and heteroaryl radicals are optionallysubstituted by 1-3 radicals of amino, C₁-C₄ alkylamino, di-(C₁-C₄alkyl)amino, C₁-C₅ alkanoylamino, (C₁-C₄ alkoxy)carbonylamino, C₁-C₄alkylsulfonylamino, C₁-C₅ alkanoyl, (C₁-C₄ alkoxy)carbonyl, hydroxy,C₁-C₄ alkoxy, C₁-C₄ alkylthio, C₁-C₄ alkylsulfinyl, C₁-C₄ alkylsulfonyl,cyano, halo, C₁-C₄ alkyl, —CF₃ or —OCF₃ radicals; (2) heterocyclylradical optionally substituted by 1-3 radicals of amino, C₁-C₄alkylamino, di-(C₁-C₄ alkyl) amino, C₁-C₅ alkanoylamino, (C₁-C₄alkoxy)carbonylamino, C₁-C₄ alkylsulfonylamino, (C₁-C₄ alkoxy)carbonyl,hydroxy, C₁-C₄ alkoxy, C₁-C₄ alkylthio, cyano, C₁-C₄ alkyl, C₁-C₂haloalkyl of 1-3 halo radicals or —OCF₃; or (3) aryl or heteroarylradical optionally substituted by 1-3 radicals of amino, C₁-C₄alkylamino, di-(C₁-C₄ alkyl)amino, C₁-C₅ alkanoylamino, (C₁-C₄alkoxy)carbonylamino, C₁-C₄ alkylsulfonylamino, (C₁-C₄ alkoxy)carbonyl,hydroxy, C₁-C₄ alkoxy, C₁-C₄ alkylthio, cyano, halo, C₁-C₄ alkyl, —CF₃or —OCF₃ radicals;

more preferably, each R³⁰ is independently (1) —CF₃ or C₁-C₄ alkylradical optionally substituted by 1-2 radicals of —CO₂R³⁴, amino, C₁-C₂alkylamino, di-(C₁-C₂ alkyl)amino, C₁-C₂ alkanoylamino, (C₁-C₄alkoxy)-carbonylamino, N-((C₁-C₄ alkoxy) carbonyl)-N-(C₁-C₄ alkyl)amino,hydroxy, C₁-C₄ alkoxy, or aryl-C₁-C₂-alkoxy, heterocyclyl, aryl orheteroaryl radicals, wherein the heterocyclyl, aryl and heteroarylradicals are optionally substituted by 1-3 radicals of amino, C₁-C₂alkylamino, di-(C₁-C₂ alkyl) amino, C₁-C₂ alkanoylamino, (C₁-C₄alkoxy)carbonylamino, C₁-C₅ alkanoyl, (C₁-C₄ alkoxy)carbonyl, hydroxy,C₁-C₄ alkoxy, halo, C₁-C₄ alkyl, —CF₃ or —OCF₃ radicals; (2)heterocyclyl radical optionally substituted by 1-2 radicals of (C₁-C₄alkoxy)carbonyl, hydroxy or C₁-C₄ alkyl; or (3) aryl or heteroarylradicals optionally substituted by 1-2 radicals of amino, C₁-C₂alkylamino, di-(C₁-C₂ alkyl)amino, C₁-C₂ alkanoylamino, hydroxy, C₁-C₂alkoxy, halo, C₁-C₄ alkyl, —CF₃ or —OCF₃ radicals;

more preferably, each R³⁰ is independently (1) heterocyclyl radicaloptionally substituted by 1-2 radicals of (C₁-C₄ alkoxy)carbonyl,hydroxy or C₁-C₄ alkyl; or (2) heteroaryl radicals optionallysubstituted by 1-2 radicals of amino, C₁-C₂ alkylamino, di-(C₁-C₂alkyl)amino, C₁-C₂ alkanoylamino, hydroxy, C₁-C₂ alkoxy, halo, C₁-C₄alkyl, —CF₃ or —OCF₃ radicals; and

most preferably, each R³⁰ is independently a heterocyclyl radicaloptionally substituted by C₁-C₄ alkyl;

wherein each R³¹ is independently hydrogen radical or (1) alkyl, alkenylor alkynyl radical optionally substituted by 1-3 radicals of —CO₂R³⁴,amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino,N-(alkoxycarbonyl)-N-(alkyl)amino, aminocarbonylamino,alkylsulfonylamino, hydroxy, alkoxy, alkylthio, alkylsulfinyl,alkylsulfonyl, cyano, halo or aralkoxy, arylalkylthio,arylalkylsulfonyl, cycloalkyl, heterocyclyl, aryl or heteroarylradicals, wherein the cycloalkyl, heterocyclyl, aryl and heteroarylradicals are optionally substituted by 1-3 radicals of amino,alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino,alkylsulfonylamino, alkanoyl, alkoxycarbonyl, hydroxy, alkoxy,alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, halo, alkyl, haloalkylor haloalkoxy; (2) heterocyclyl radical optionally substituted by 1-3radicals of amino, alkylamino, dialkylamino, alkanoylamino,alkoxycarbonylamino, alkylsulfonylamino, alkoxycarbonyl, hydroxy,alkoxy, alkylthio, cyano, alkyl, haloalkyl or haloalkoxy; or (3) aryl orheteroaryl radical optionally substituted by 1-3 radicals of amino,alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino,alkylsulfonylamino, alkoxycarbonyl, hydroxy, alkoxy, alkylthio, cyano,halo, azido, alkyl, haloalkyl or haloalkoxy;

preferably, each R³¹ is independently hydrogen radical or (1) C₁-C₈alkyl, C₂-C₈ alkenyl or C₂-C₈ alkynyl radical optionally substituted by1-3 radicals of —CO₂R³⁴, amino, C₁-C₄ alkylamino, di-(C₁-C₄ alkyl)amino,C₁-C₅ alkanoylamino, (C₁-C₄ alkoxy)carbonylamino, N-((C₁-C₄ alkoxy)carbonyl)-N-(C₁-C₄ alkyl)amino, aminocarbonylamino, C₁-C₄alkylsulfonylamino, hydroxy, C₁-C₄ alkoxy, C₁-C₄ alkylthio, C₁-C₄alkylsulfinyl, C₁-C₄ alkylsulfonyl, cyano, halo, aryl-C₁-C₄-alkoxy,aryl-C₁-C₄-alkylthio, aryl-C₁-C₄-alkylsulfonyl, C₃-C₈ cycloalkyl,heterocyclyl, aryl or heteroaryl radicals, wherein the cycloalkyl,heterocyclyl, aryl and heteroaryl radicals are optionally substituted by1-3 radicals of amino, C₁-C₄ alkylamino, di-(C₁-C₄ alkyl)amino, C₁-C₅alkanoylamino, (C₁-C₄ alkoxy) carbonylamino, C₁-C₄ alkylsulfonylamino,C₁-C₅ alkanoyl, (C₁-C₄ alkoxy)carbonyl, hydroxy, C₁-C₄ alkoxy, C₁-C₄alkylthio, C₁-C₄ alkylsulfinyl, C₁-C₄ alkylsulfonyl, cyano, halo, C₁-C₄alkyl, C₁-C₄ haloalkyl of 1-3 halo radicals or C₁-C₄ haloalkoxy of 1-3halo radicals; (2) heterocyclyl radical optionally substituted by 1-3radicals of amino, C₁-C₄ alkylamino, di-(C₁-C₄ alkyl)amino, C₁-C₅alkanoylamino, (C₁-C₄ alkoxy)carbonylamino, C₁-C₄ alkylsulfonylamino,(C₁-C₄ alkoxy)carbonyl, hydroxy, C₁-C₄ alkoxy, C₁-C₄ alkylthio, cyano,C₁-C₄ alkyl, C₁-C₄ haloalkyl of 1-3 halo radicals or C₁-C₄ haloalkoxy of1-3 halo radicals; or (3) aryl or heteroaryl radical optionallysubstituted by 1-3 radicals of amino, C₁-C₄ alkylamino, di-(C₁-C₄ alkyl)amino, C₁-C₅ alkanoylamino, (C₁-C₄ alkoxy)carbonylamino, C₁-C₄alkylsulfonylamino, (C₁-C₄ alkoxy)carbonyl, hydroxy, C₁-C₄ alkoxy, C₁-C₄alkylthio, cyano, halo, azido, C₁-C₄ alkyl, C₁-C₄ haloalkyl of 1-3 haloradicals or C₁-C₄ haloalkoxy of 1-3 halo radicals;

more preferably, each R³¹ is independently hydrogen radical or (1) C₁-C₆alkyl radical optionally substituted by 1-3 radicals of —CO₂R³⁴, amino,C₁-C₄ alkylamino, di-(C₁-C₄ alkyl)amino, C₁-C₅ alkanoylamino, (C₁-C₄alkoxy)carbonylamino, N-((C₁-C₄ alkoxy)carbonyl)-N-(C₁-C₄ alkyl)amino,aminocarbonylamino, C₁-C₄ alkylsulfonylamino, hydroxy, C₁-C₄ alkoxy,C₁-C₄ alkylthio, C₁-C₄ alkylsulfinyl, C₁-C₄ alkylsulfonyl, cyano, halo,aryl-C₁-C₄-alkoxy, aryl-C₁-C₄-alkylthio, aryl-C₁-C₄-alkylsulfonyl, C₃-C₈cycloalkyl, heterocyclyl, aryl or heteroaryl radicals, wherein thecycloalkyl, heterocyclyl, aryl and heteroaryl radicals are optionallysubstituted by 1-3 radicals of amino, C₁-C₄ alkylamino, di-(C₁-C₄ alkyl)amino, C₁-C₅ alkanoylamino, (C₁-C₄ alkoxy)carbonylamino, C₁-C₄alkylsulfonylamino, C₁-C₅ alkanoyl, (C₁-C₄ alkoxy)carbonyl, hydroxy,C₁-C₄ alkoxy, C₁-C₄ alkylthio, C₁-C₄ alkylsulfinyl, C₁-C₄ alkylsulfonyl,cyano, halo, C₁-C₄ alkyl, C₁-C₄ haloalkyl of 1-3 halo radicals or C₁-C₄haloalkoxy of 1-3 halo radicals; (2) heterocyclyl radical optionallysubstituted by 1-3 radicals of amino, C₁-C₄ alkylamino, di-(C₁-C₄alkyl)amino, C₁-C₅ alkanoylamino, (C₁-C₄ alkoxy)carbonylamino, C₁-C₄alkylsulfonylamino, (C₁-C₄ alkoxy)carbonyl, hydroxy, C₁-C₄ alkoxy, C₁-C₄alkylthio, cyano, C₁-C₄ alkyl, C₁-C₄ haloalkyl of 1-3 halo radicals orC₁-C₄ haloalkoxy of 1-3 halo radicals; or (3) aryl or heteroaryl radicaloptionally substituted by 1-3 radicals of amino, C₁-C₄ alkylamino,di-(C₁-C₄ alkyl)amino, C₁-C₅ alkanoylamino, (C₁-C₄ alkoxy)carbonylamino, C₁-C₄ alkylsulfonylamino, (C₁-C₄ alkoxy)carbonyl,hydroxy, C₁-C₄ alkoxy, C₁-C₄ alkylthio, cyano, halo, azido, C₁-C₄ alkyl,C₁-C₄ haloalkyl of 1-3 halo radicals or C₁-C₄ haloalkoxy of 1-3 haloradicals;

more preferably, each R³¹ is independently hydrogen radical or (1) C₁-C₆alkyl radical optionally substituted by 1-3 radicals of —CO₂R³⁴, amino,C₁-C₄ alkylamino, di-(C₁-C₄ alkyl)amino, C₁-C₅ alkanoylamino, (C₁-C₄alkoxy)carbonylamino, N-((C₁-C₄ alkoxy)carbonyl)-N-(C₁-C₄ alkyl)amino,aminocarbonylamino, C₁-C₄ alkylsulfonylamino, hydroxy, C₁-C₄ alkoxy,C₁-C₄ alkylthio, C₁-C₄ alkylsulfinyl, C₁-C₄ alkylsulfonyl, cyano, halo,aryl-C₁-C₄-alkoxy, aryl-C₁-C₄-alkylthio, aryl-C₁-C₄-alkylsulfonyl, C₃-C₈cycloalkyl, heterocyclyl, aryl or heteroaryl radicals, wherein thecycloalkyl, heterocyclyl, aryl and heteroaryl radicals are optionallysubstituted by 1-3 radicals of amino, C₁-C₄ alkylamino, di-(C₁-C₄alkyl)amino, C₁-C₅ alkanoylamino, (C₁-C₄ alkoxy)carbonylamino, C₁-C₄alkylsulfonylamino, C₁-C₅ alkanoyl, (C₁-C₄ alkoxy)carbonyl, hydroxy,C₁-C₄ alkoxy, C₁-C₄ alkylthio, C₁-C₄ alkylsulfinyl, C₁-C₄ alkylsulfonyl,cyano, halo, C₁-C₄ alkyl, —CF₃ or —OCF₃ radicals; (2) heterocyclylradical optionally substituted by 1-3 radicals of amino, C₁-C₄alkylamino, di-(C₁-C₄ alkyl) amino, C₁-C₅ alkanoylamino, (C₁-C₄alkoxy)carbonylamino, C₁-C₄ alkylsulfonylamino, (C₁-C₄ alkoxy)carbonyl,hydroxy, C₁-C₄ alkoxy, C₁-C₄ alkylthio, cyano, C₁-C₄ alkyl, C₁-C₂haloalkyl of 1-3 halo radicals or —OCF₃; or (3) aryl or heteroarylradical optionally substituted by 1-3 radicals of amino, C₁-C₄alkylamino, di-(C₁-C₄ alkyl)amino, C₁-C₅ alkanoylamino, (C₁-C₄alkoxy)carbonylamino, C₁-C₄ alkylsulfonylamino, (C₁-C₄ alkoxy)carbonyl,hydroxy, C₁-C₄ alkoxy, C₁-C₄ alkylthio, cyano, halo, C₁-C₄ alkyl, —CF₃or —OCF₃ radicals;

more preferably, R³¹ is independently hydrogen radical or (1) —CF₃ orC₁-C₄ alkyl radical optionally substituted by 1-2 radicals of hydroxy,C₁-C₂ alkoxy or aryl-C₁-C₂-alkoxy, aryl or heteroaryl radicals, whereinthe aryl and heteroaryl radicals are optionally substituted by 1-2radicals of amino, C₁-C₂ alkylamino, di-(C₁-C₂ alkyl) amino, C₁-C₂alkanoylamino, (C₁-C₄ alkoxy)carbonylamino, C₁-C₅ alkanoyl, (C₁-C₄alkoxy)carbonyl, hydroxy, C₁-C₄ alkoxy, halo, C₁-C₄ alkyl, —CF₃ or —OCF₃radicals; or (2) aryl or heteroaryl radical optionally substituted by1-2 radicals of amino, C₁-C₂ alkylamino, di-(C₁-C₂ alkyl)amino, C₁-C₂alkanoylamino, hydroxy, C₁-C₂ alkoxy, halo, C₁-C₄ alkyl, —CF₃ or —OCF₃radicals; and

most preferably, each R³¹ is independently hydrogen radical or (1) —CF₃or C₁-C₄ alkyl radical optionally substituted by 1-2 radicals of aryl orheteroaryl radicals; or (2) aryl or heteroaryl radical;

wherein each R³² is independently (1) hydrogen radical; (2) alkyl,alkenyl or alkynyl radical optionally substituted by 1-3 radicals ofamino, alkylamino, dialkylamino, hydroxy, alkoxy, alkylthio, cyano orhalo; or (3) aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl,heterocyclylalkyl, cycloalkyl or cycloalkylalkyl radicals optionallysubstituted by 1-3 radicals of amino, alkylamino, dialkylamino, hydroxy,alkoxy, alkylthio, cyano, alkyl, haloalkyl or haloalkoxy;

preferably, each R³² is independently (1) hydrogen radical; (2) C₁-C₈alkyl, C₂-C₈ alkenyl or C₂-C₈ alkynyl radical optionally substituted by1-3 radicals of amino, C₁-C₄ alkylamino, di-(C₁-C₄-alkyl)amino, hydroxy,C₁-C₄ alkoxy, C₁-C₄ alkylthio, cyano or halo; or (3) aryl, heteroaryl,aryl-C₁-C₄-alkyl, heteroaryl-C₁-C₄-alkyl, heterocyclyl,heterocyclyl-C₁-C₄-alkyl, C₃-C₈ cycloalkyl orC₃-C₈-Cycloalkyl-C₁-C₄-alkyl radical optionally substituted by 1-3radicals of amino, C₁-C₄ alkylamino, di-(C₁-C₄-alkyl)amino, hydroxy,C₁-C₄ alkoxy, C₁-C₄ alkylthio, cyano, C₁-C₄ alkyl, C₁-C₄ haloalkyl of1-3 halo radicals or C₁-C₄ haloalkoxy of 1-3 halo radicals;

more preferably, each R³² is independently hydrogen or C₁-C₄ alkylradical; and most preferably, each R³² is independently a hydrogen ormethyl radical;

wherein each R³³ is independently (1) hydrogen radical; (2) alkylradical optionally substituted by a radical of heterocyclyl, aryl orheteroaryl which is optionally substituted by 1-3 radicals of amino,alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino,alkylsulfonylamino, hydroxy, alkoxy, alkylthio, alkylsulfinyl,alkylsulfonyl, cyano, halo, alkyl, haloalkyl or haloalkoxy; or (3)heterocyclyl, aryl or heteroaryl radical optionally substituted by 1-3radicals of amino, alkylamino, dialkylamino, alkanoylamino,alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio,alkylsulfinyl, alkylsulfonyl, cyano, halo, alkyl, haloalkyl orhaloalkoxy;

preferably, each R³³ is independently (1) hydrogen radical; (2) C₁-C₄alkyl radical optionally substituted by a radical of heterocyclyl, arylor heteroaryl which is optionally substituted by 1-3 radicals of amino,C₁-C₄ alkylamino, di-(C₁-C₄ alkyl)amino, C₁-C₅ alkanoyl amino, (C₁-C₄alkoxy)carbonylamino, C₁-C₄ alkylsulfonyl amino, hydroxy, C₁-C₄ alkoxy,C₁-C₄ alkylthio, C₁-C₄ alkylsulfinyl, C₁-C₄ alkylsulfonyl, cyano, halo,C₁-C₄ alkyl, C₁-C₄ haloalkyl of 1-3 halo radicals or C₁-C₄ haloalkoxy of1-3 halo radicals; or (3) heterocyclyl, aryl or heteroaryl radicaloptionally substituted by 1-3 radicals of amino, C₁-C₄ alkylamino,di-(C₁-C₄ alkyl) amino, C₁-C₅ alkanoylamino, (C₁-C₄alkoxy)carbonylamino, C₁-C₄ alkylsulfonylamino, hydroxy, C₁-C₄ alkoxy,C₁-C₄ alkylthio, C₁-C₄ alkylsulfinyl, C₁-C₄ alkylsulfonyl, cyano, halo,C₁-C₄ alkyl, C₁-C₄ haloalkyl of 1-3 halo radicals or C₁-C₄ haloalkoxy of1-3 halo radicals;

more preferably, each R³³ is independently hydrogen or C₁-C₄ alkylradical; and most preferably, each R³³ is independently a hydrogen ormethyl radical; and

wherein each R³⁴ is independently hydrogen, alkyl, aryl, heteroaryl,arylalkyl or heteroarylalkyl radical, wherein the aryl and heteroarylradicals are optionally substituted by 1-3 radicals of amino,alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino,alkylsulfonylamino, hydroxy, alkoxy, alkylthio, alkylsulfinyl,alkylsulfonyl, cyano, halo, alkyl, haloalkyl or haloalkoxy;

preferably, each R³⁴ is independently hydrogen or C₁-C₄ alkyl, aryl,heteroaryl, aryl-C₁-C₄-alkyl or heteroaryl-C₁-C₄-alkyl radical, whereinthe aryl and heteroaryl radicals are optionally substituted by 1-3radicals of amino, C₁-C₄ alkylamino, di-(C₁-C₄ alkyl)amino, C₁-C₅alkanoylamino, (C₁-C₄ alkoxy)carbonylamino, C₁-C₄ alkylsulfonylamino,hydroxy, C₁-C₄ alkoxy, C₁-C₄ alkylthio, C₁-C₄ alkylsulfinyl, C₁-C₄alkylsulfonyl, cyano, halo, C₁-C₄ alkyl, C₁-C₄ haloalkyl of 1-3 haloradicals or C₁-C₄ haloalkoxy of 1-3 halo radicals;

more preferably, each R³⁴ is independently hydrogen or C₁-C₄ alkylradical; and most preferably, each R³⁴ is independently a hydrogen ormethyl radical.

The symbols used above have the following meanings:

—CR^(x)R^(y)— =

—C(O)— =

—NR^(x)R^(y) =

—C(NR)— =

—NR— =

—S(O)₂— =

For example:

An aryl radical optionally substituted by an optionally substitutedmonocyclic heteroaryl or heterocyclyl radical of 5-6 ring members whichis optionally substituted by a phenyl radical or monocyclic heteroarylradical of 5-6 ring members means an aryl radical which is optionallysubstituted by (a) a monocyclic heteroaryl radical of 5-6 ring membersoptionally substituted by a phenyl radical or monocyclic heteroarylradical of 5-6 ring members; or (b) a monocyclic heterocyclyl radical of5-6 ring members optionally substituted by a phenyl radical ormonocyclic heteroaryl radical of 5-6 ring members.

A heteroaryl radical optionally substituted by an optionally substitutedphenyl or a monocyclic heteroaryl or heterocyclyl radical of 5-6 ringmembers which is optionally substituted by a phenyl radical ormonocyclic heteroaryl radical of 5-6 ring members means a heteroarylradical which is optionally substituted by (a) a phenyl radicaloptionally substituted by a phenyl radical or monocyclic heteroarylradical of 5-6 ring members; (b) a monocyclic heteroaryl radical of 5-6ring members optionally substituted by a phenyl radical or monocyclicheteroaryl radical of 5-6 ring members; or (c) a monocyclic heterocyclylradical of 5-6 ring members optionally substituted by a phenyl radicalor monocyclic heteroaryl radical of 5-6 ring members.

The compounds of this invention have in general several asymmetriccenters and are depicted in the form of racemic mixtures. This inventionis intended to encompass racemic mixtures, partially racemic mixturesand separate enantiomers and diasteromers. Preferably, the absoluteconfiguration of the carboxylic acid group is (R). Preferably, therelative configuration of the carboxylic acid group and —NR¹¹R³³ is cis,i.e., the carboxylic acid and —NR¹¹R³³ are on the same face of the ringsystem.

Compounds of interest include the following:

3-amino-1-(4-methoxyphenylsulfonyl)azepane-2-carboxylic acid

3-(phenylmethylsulfonylamino)-1-(4-methoxyphenylsulfonyl)azepane-2-carboxylicacid

3-((2-aminophenyl)methylsulfonylamino)-1-(4-methoxyphenylsulfonyl)azepane-2-carboxylicacid

cis-1-(4-Methoxy-benzenesulfonyl)-3-(phenylmethanesulfonylamino)-heptamethyleneimine-2-carboxylic acid

trans-1-(4-Methoxy-benzenesulfonyl)-3-(phenylmethanesulfonylamino)-heptamethyleneimine-2-carboxylic acid

3-Benzyloxycarbonylamino-1-(4-methoxy-benzenesulfonyl)-1H-azepane-2-carboxylicacid

3-amino-1-(4-methoxyphenylsulfonyl)-2,3,4,7-tetrahydro-1H-azepine-2-carboxylicacid

3-(methylsulfonylamino)-1-(4-methoxyphenylsulfonyl)-2,3,4,7-tetrahydro-1H-azepine-2-carboxylicacid

3-(phenylsulfonylamino)-1-(4-methoxyphenylsulfonyl)-2,3,4,7-tetrahydro-1H-azepine-2-carboxylicacid

3-(naphth-2-ylsulfonylamino)-1-(4-methoxyphenylsulfonyl)-2,3,4,7-tetrahydro-1H-azepine-2-carboxylic acid

3-(naphth-1-ylsulfonylamino)-1-(4-methoxyphenylsulfonyl)-2,3,4,7-tetrahydro-1H-azepine-2-carboxylic acid

3-(phenylmethylsulfonylamino)-1-(4-methoxyphenylsulfonyl)-2,3,4,7-tetrahydro-1H-azepine-2-carboxylic acid

3-((2-nitrophenyl)methylsulfonylamino)-1-(4-methoxyphenylsulfonyl)-2,3,4,7-tetrahydro-1H-azepine-2-carboxylic acid

3-((2-phenylethenyl)sulfonylamino)-1-(4-methoxyphenylsulfonyl)-2,3,4,7-tetrahydro-1H-azepine-2-carboxylic acid

3-((4-iodophenyl)sulfonylamino)-1-(4-methoxyphenylsulfonyl)-2,3,4,7-tetrahydro-1H-azepine-2-carboxylic acid

3-(4-(4-chlorophenyl)phenyl)sulfonylamino)-1-(4-methoxyphenylsulfonyl)-2,3,4,7-tetrahydro-1H-azepine-2-carboxylic acid

3-(phenylmethoxycarbonylamino)-1-(4-methoxyphenylsulfonyl)-2,3,4,7-tetrahydro-1H-azepine-2-carboxylic acid

3-((4-trifluoromethylphenyl)methoxycarbonylamino)-1-(4-methoxyphenylsulfonyl)-2,3,4,7-tetrahydro-1H-azepine-2-carboxylicacid

3-((4-Chlorophenyl)methoxycarbonylamino)-1-(4-methoxyphenylsulfonyl)-2,3,4,7-tetrahydro-1H-azepine-2-carboxylic acid

3-((3,5-dichlorophenyl)methoxycarbonylamino)-1-(4-methoxyphenylsulfonyl)-2,3,4,7-tetrahydro-1H-azepine-2-carboxylicacid

1-(4-Methoxy-benzenesulfonyl)-3-(4-Chlorophenyl-phenylsulfonylamino)-2,3,4,7-tetrahydro-1H-azepine-2-carboxylicacid

1-(4-Methoxy-benzenesulfonyl)-3-(4-chlorophenyl-methanesulfonylamino)-2,3,4,7-tetrahydro-1H-azepine-2-carboxylicacid

1-(4-Methoxy-benzenesulfonyl)-3(R)-(phenylmethanesulfonylamino)-heptamethyleneimine-2(S)-carboxylic acid

trans-1-(4-Methoxy-benzenesulfonyl)-3(R)-(phenylmethanesulfonylamino)-heptamethyleneimine-2(R)-carboxylic acid.

As utilized herein, the following terms shall have the followingmeanings:

“Alkyl”, alone or in combination, means a straight-chain orbranched-chain alkyl radical containing preferably 1-15 carbon atoms(C₁-C₁₅), more preferably 1-8 carbon atoms (C₁-C₈), even more preferably1-6 carbon atoms (C₁-C₆), yet more preferably 1-4 carbon atoms (C₁-C₄),still more preferably 1-3 carbon atoms (C₁-C₃), and most preferably 1-2carbon atoms (C₁-C₂). Examples of such radicals include methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl,isoamyl, hexyl, octyl and the like.

“Alkenyl”, alone or in combination, means a straight-chain orbranched-chain hydrocarbon radical having one or more double bonds,preferably 1-2 double bonds and more preferably one double bond, andcontaining preferably 2-15 carbon atoms (C₂-C₁₅), more preferably 2-8carbon atoms (C₂-C₈), even more preferably 2-6 carbon atoms (C₂-C₆), yetmore preferably 2-4 carbon atoms (C₂-C₄), and still more preferably 2-3carbon atoms (C₂-C₃). Examples of such alkenyl radicals include ethenyl,propenyl, 2-methylpropenyl, 1,4-butadienyl and the like.

“Alkynyl”, alone or in combination, means a straight-chain or branchedchain hydrocarbon radical having one or more triple bonds, preferably1-2 triple bonds and more preferably one triple bond, and containingpreferably 2-15 carbon atoms (C₂-C₁₅), more preferably 2-8 carbon atoms(C₂-C₈), even more preferably 2-6 carbon atoms (C₂-C₆), yet morepreferably 2-4 carbon atoms (C₂-C₄), and still more preferably 2-3carbon atoms (C₂-C₃). Examples of such alkynyl radicals include ethynyl,propynyl (propargyl), butynyl and the like.

“Alkoxy”, alone or in combination, means a radical of the type “R—O—”wherein “R” is an alkyl radical as defined above and “O” is an oxygenatom. Examples of such alkoxy radicals include methoxy, ethoxy,n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy andthe like.

“Alkoxycarbonyl”, alone or in combination, means a radical of the type“R—O—C(O)—” wherein “R—O—” is an alkoxy radical as defined above and“C(O)” is a carbonyl radical.

“Alkoxycarbonylamino”, alone or in combination, means a radical of thetype “R—O—C(O)—NH—” wherein “R—O—C(O)” is an alkoxycarbonyl radical asdefined above, wherein the amino radical may optionally be substituted,such as with alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl and thelike.

“Alkylthio”, alone or in combination, means a radical of the type “R—S—”wherein “R” is an alkyl radical as defined above and “S” is a sulfuratom. Examples of such alkylthio radicals include methylthio, ethylthio,n-propylthio, isopropylthio, n-butylthio, iso-butylthio, sec-butylthio,tert-butylthio and the like.

“Alkylsulfinyl”, alone or in combination, means a radical of the type“R—S(O)—” wherein “R” is an alkyl radical as defined above and “S(O)” isa mono-oxygenated sulfur atom. Examples of such alkylsulfinyl radicalsinclude methylsulfinyl, ethylsulfinyl, n-propylsulfinyl,isopropylsulfinyl, n-butylsulfinyl, iso-butylsulfinyl,sec-butylsulfinyl, tert-butylsulfinyl and the like.

“Alkylsulfonyl”, alone or in combination, means a radical of the type“R—S(O)₂—” wherein “R” is an alkyl radical as defined above and “S(O)₂”is a di-oxygenated sulfur atom. Examples of such alkylsulfonyl radicalsinclude methylsulfonyl, ethylsulfonyl, n-propylsulfonyl,isopropylsulfonyl, n-butylsulfonyl, iso-butylsulfonyl,sec-butylsulfonyl, tert-butylsulfonyl and the like.

“Alkylsulfonylamino”, alone or in combination, means a radical of thetype “R—S(O)₂—NH—” wherein “R—S(O)₂—” is an alkylsulfonyl radical asdefined above, wherein the amino radical may optionally be substituted,such as with alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl and thelike.

“Aryl”, alone or in combination, means a phenyl, biphenyl or naphthylradical which is optionally substituted with one or more substituentsselected from alkyl, alkoxy, halogen, hydroxy, amino, azido, nitro,cyano, haloalkyl, carboxy, alkoxycarbonyl, cycloalkyl, heterocyclo,alkanoylamino, amido, amidino, alkoxycarbonylamino, N-alkylamidino,alkylamino, dialkylamino, N-alkylamido, N,N-dialkylamido,aralkoxycarbonylamino, alkylthio, alkylsulfinyl, alkylsulfonyl and thelike. Examples of aryl radicals are phenyl, p-tolyl, 4-methoxyphenyl,4-(tert-butoxy)phenyl, 3-methyl-4-methoxyphenyl, 4-CF₃-phenyl,4-fluorophenyl, 4-Chlorophenyl, 3-nitrophenyl, 3-aminophenyl,3-acetamidophenyl, 4-acetamidophenyl, 2-methyl-3-acetamidophenyl,2-methyl-3-aminophenyl, 3-methyl-4-aminophenyl, 2-amino-3-methylphenyl,2,4-dimethyl-3-aminophenyl, 4-hydroxyphenyl, 3-methyl-4-hydroxyphenyl,4-(4-methoxyphenyl)phenyl, 1-naphthyl, 2-naphthyl, 3-amino-1-naphthyl,2-methyl-3-amino-1-naphthyl, 6-amino-2-naphthyl,4,6-dimethoxy-2-naphthyl, piperazinylphenyl and the like.

“Aryl-alkyl”, alone or in combination, means an alkyl radical as definedabove in which at least one hydrogen atom, preferably 1-2, is replacedby an aryl radical as defined above, such as benzyl, 1-, 2-phenylethyl,dibenzylmethyl, hydroxyphenylmethyl, methylphenylmethyl, diphenylmethyl,dichlorophenylmethyl, 2-naphthylmethyl, 4-methoxyphenylmethyl and thelike.

“Aryl-alkoxyl”, alone or in combination, means an alkoxy radical asdefined above in which at least one hydrogen atom, preferably 1-2, isreplaced by an aryl radical as defined above, such as benzyloxy, 1-,2-phenylethoxy, dibenzylmethoxy, hydroxyphenylmethoxy,methylphenylmethoxy, dichlorophenylmethoxy, 4-methoxyphenylmethoxy andthe like.

“Aryloxy”, alone or in combination, means a radical of the type “R—O—”wherein “R” is an aryl radical as defined above.

“Aroyl”, alone or in combination, means a radical of the type “R—C(O)—”wherein “R” is an aryl radical as defined above and “—C(O)—” is acarbonyl.

“Alkanoyl”, alone or in combination, means a radical of the type“R—C(O)—” wherein “R” is an alkyl radical as defined above and “—C(O)—”is a carbonyl radical. Examples of such alkanoyl radicals includeacetyl, trifluoroacetyl, hydroxyacetyl, propionyl, butyryl, valeryl,4-methylvaleryl, and the like.

“Alkanoylamino”, alone or in combination, means a radical of the type“R—C(O)—NH—” wherein “R—C(O)—” is an alkanoyl radical as defined above,wherein the amino radical may optionally be substituted, such as withalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl and the like.

“Aminocarbonylamino”, alone or in combination, means an aminosubstituted carbonyl substituted on a second amino (ureido) radical,wherein each amino radical may optionally be mono- or di-substituted,such as with alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl,alkanoyl, alkoxycarbonyl, aralkoxycarbonyl and the like.

“Benzo”, alone or in combination, means the divalent radicalC₆H₄=derived from benzene.

“Bicyclic” as used herein is intended to include both fused ringsystems, such as naphthyl and β-carbolinyl, and substituted ringsystems, such as biphenyl, phenylpyridyl, naphthyl anddiphenylpiperazinyl.

“Cycloalkyl”, alone or in combination, means a saturated or partiallysaturated, preferably one double bond, monocyclic, bicyclic or tricyclicalkyl radical, preferably monocyclic, containing preferably 3-10 carbonatoms (C₃-C₁₀), more preferably 3-8 carbon atoms (C₃-C₈), even morepreferably 3-6 carbon atoms (C₃-C₆), which is optionally be benzo fusedand which is optionally substituted as defined herein with respect tothe definition of aryl. Examples of such cycloalkyl radicals includecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, dihydroxycyclohexyl,cycloheptyl, octahydronaphthyl, tetrahydronaphthyl,dimethoxytetrahydronaphthyl, 2,3-dihydro-1H-indenyl and the like.

“Cycloalkylalkyl”, alone or in combination, means an alkyl radical asdefined above which is substituted by a cycloalkyl radical as definedabove. Examples of such cycloalkylalkyl radicals includecyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl,cyclohexylmethyl, 1-cyclopentylethyl, 1-cyclohexylethyl,2-cyclopentylethyl, 2-cyclohexylethyl, hydroxycyclopentylpropyl,tetrahydronaphthylpropyl, cyclohexylbutyl and the like.

“Heteroatoms” means nitrogen, oxygen and sulfur heteroatoms.

“Heterocyclyl”, alone or in combination, means a saturated or partiallyunsaturated, preferably one double bond, monocyclic or bicyclic,preferably monocyclic, heterocycle radical containing at least one,preferably 1 to 4, more preferably 1 to 3, even more preferably 1-2,nitrogen, oxygen or sulfur atom ring member and having preferably 3-8ring members in each ring, more preferably 5-8 ring members in each ringand even more preferably 5-6 ring members in each ring.

“Heterocyclyl” is intended to include sulfone and sulfoxide derivativesof sulfur ring members and N-oxides of tertiary nitrogen ring members,and carbocyclic fused, preferably 3-6 ring carbon atoms and morepreferably 5-6 ring carbon atoms, and benzo fused ring systems.“Heterocyclyl” radicals may optionally be substituted on at least one,preferably 1-4, more preferably 1-3, even more preferably 1-2, carbonatoms by halogen, alkyl, alkoxy, hydroxy, oxo, thioxo, aryl, aralkyl,heteroaryl, heteroaralkyl, amidino, N-alkylamidino, alkoxycarbonylamino,alkylsulfonylamino and the like, and/or on a secondary nitrogen atom byhydroxy, alkyl, aralkoxycarbonyl, alkanoyl, alkoxycarbonyl,heteroaralkyl, aryl or aralkyl radicals. More preferably,“heterocyclyl”, alone or in combination, is a radical of a monocyclic orbicyclic saturated heterocyclic ring system having 5-8 ring members perring, wherein 1-3 ring members are oxygen, sulfur or nitrogenheteroatoms, which is optionally partially unsaturated or benzo-fusedand optionally substituted by 1-2 oxo or thioxo radicals. Examples ofsuch heterocyclyl radicals include pyrrolidinyl, piperidinyl,piperazinyl, morpholinyl, thiamorpholinyl, 4-benzyl-piperazin-1-yl,pyrimidinyl, tetrahydrofuryl, pyrazolidonyl, pyrazolinyl, pyridazinonyl,pyrrolidonyl, tetrahydrothienyl and its sulfoxide and sulfonederivatives, 2,3-dihydroindolyl, tetrahydroquinolinyl,1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydro-1-oxo-isoquinolinyl,2,3-dihydrobenzofuryl, benzopyranyl, methylenedioxyphenyl,ethylenedioxyphenyl and the like.

“Heterocyclylalkyl”, alone or in combination, means an alkyl radical asdefined above in which at least one hydrogen atom, preferably 1-2, isreplaced by a heterocyclyl radical as defined above, such aspyrrolidinylmethyl, tetrahydrothienylmethyl, piperidinylethyl and thelike.

“Heteroaryl”, alone or in combination, means a monocyclic or bicyclic,preferably monocyclic, aromatic heterocycle radical, having at leastone, preferably 1 to 4, more preferably 1 to 3, even more preferably1-2, nitrogen, oxygen or sulfur atom ring members and having preferably5-6 ring members in each ring, which is optionally benzo fused orsaturated carbocyclic fused, preferably 3-4 carbon atoms (C₃-C₄) to form5-6 ring membered rings and which is optionally substituted as definedabove with respect to the definitions of aryl and heterocyclyl. Morepreferably, “heteroaryl”, alone or in combination, is a radical of amonocyclic or bicyclic aromatic heterocyclic ring system having 5-6 ringmembers per ring, wherein 1-3 ring members are oxygen, sulfur ornitrogen heteroatoms, which is optionally benzo-fused or saturatedC₃-C₄-Carbocyclic-fused. Examples of such heteroaryl groups includeimidazolyl, 1-benzyloxycarbonylimidazol-4-yl, pyrrolyl, pyrazolyl,pyridyl, 2-(1-piperidinyl)pyridyl, 2-(4-benzylpiperazin-1-yl)-1-pyridinyl, pyrazinyl, triazolyl, furyl, thienyl,oxazolyl, thiazolyl, indolyl, quinolinyl, 1-oxido-2-quinolinyl,isoquinolinyl, 5,6,7,8-tetrahydroquinolyl,5,6,7,8-tetrahydroisoquinolinyl, quinoxalinyl, benzothiazolyl,β-carbolinyl, benzofuryl, benzimidazolyl, benzoxazolyl and the like.

“Heteroaroyl”, alone or in combination, means a radical of the type“R—C(O)—” wherein “R” is an heteroaryl radical as defined above and“—C(O)—” is a carbonyl.

“Heteroaryl-alkyl”, alone or in combination, means an alkyl radical asdefined above in which at least one hydrogen atom, preferably 1-2, isreplaced by a heteroaryl radical as defined above, such as3-furylpropyl, 2-pyrrolyl propyl, chloroquinolinylmethyl,2-thienylethyl, pyridylmethyl, 1-imidazolylethyl and the like.

“Halogen” and “halo”, alone or in combination, means fluoro, chloro,bromo or iodo radicals.

“Haloalky”, alone or in combination, means an alkyl radical as definedabove in which at least one hydrogen atom, preferably 1-3, is replacedby a halogen radical, more preferably fluoro or chloro radicals.Examples of such haloalkyl radicals include 1,1,1-trifluoroethyl,chloromethyl, 1-bromoethyl, fluoromethyl, difluoromethyl,trifluoromethyl, bis(trifluoromethyl)methyl and the like.

“Haloalkoxyl”, alone or in combination, means an alkoxy radical asdefined above in which at least one hydrogen atom, preferably 1-3, isreplaced by a halogen radical, more preferably fluoro or chlororadicals. Examples of such haloalkoxy radicals include2,2,2-trifluoroethoxy, chloromethoxy, 2-bromoethoxy, fluoromethoxy,difluoromethoxy, trifluoromethoxy, bis(trifluoromethyl)methoxy and thelike.

“Sulfinyl”, alone or in combination, means a diradical of the type“—S(O)—” wherein “S(O)” is a mono-oxygenated sulfur atom. “Sulfonyl”,alone or in combination, means a diradical of the type “—S(O)₂—” wherein“S(O)₂” is a di-oxygenated sulfur atom.

“Leaving group” generally refers to groups readily displaceable by anucleophile, such as an amine, a thiol or an alcohol nucleophile. Suchleaving groups are well known in the art. Examples of such leavinggroups include, but are not limited to, N-hydroxysuccinimide,N-hydroxybenzotriazole, halides, triflates, tosylates and the like.Preferred leaving groups are indicated herein where appropriate.

“Protecting group” generally refers to groups well known in the artwhich are used to prevent selected reactive groups, such as carboxy,amino, hydroxy, mercapto and the like, from undergoing undesiredreactions, such as nucleophilic, electrophilic, oxidation, reduction andthe like. Preferred protecting groups are indicated herein whereappropriate. Examples of amino protecting groups include, but are notlimited to, aralkyl, substituted aralkyl, cycloalkenylalkyl andsubstituted cycloalkenyl alkyl, allyl, substituted allyl, acyl,alkoxycarbonyl, aralkoxycarbonyl, silyl and the like. Examples ofaralkyl include, but are not limited to, benzyl, ortho-methylbenzyl,trityl and benzhydryl, which can be optionally substituted with halogen,alkyl, alkoxy, hydroxy, nitro, acylamino, acyl and the like, and salts,such as phosphonium and ammonium salts. Examples of aryl groups includephenyl, naphthyl, indanyl, anthracenyl, 9-(9-phenylfluorenyl),phenanthrenyl, durenyl and the like. Examples of cycloalkenylalkyl orsubstituted cycloalkylenylalkyl radicals, preferably have 6-10 carbonatoms, include, but are not limited to, cyclohexenyl methyl and thelike. Suitable acyl, alkoxycarbonyl and aralkoxycarbonyl groups includebenzyloxycarbonyl, t-butoxycarbonyl, iso-butoxycarbonyl, benzoyl,substituted benzoyl, butyryl, acetyl, tri-fluoroacetyl, tri-chloroacetyl, phthaloyl and the like. A mixture of protecting groups can beused to protect the same amino group, such as a primary amino group canbe protected by both an aralkyl group and an aralkoxycarbonyl group.Amino protecting groups can also form a heterocyclic ring with thenitrogen to which they are attached, for example,1,2-bis(methylene)benzene, phthalimidyl, succinimidyl, maleimidyl andthe like and where these heterocyclic groups can further includeadjoining aryl and cycloalkyl rings. In addition, the heterocyclicgroups can be mono-, di- or tri-substituted, such as nitrophthalimidyl.Amino groups may also be protected against undesired reactions, such asoxidation, through the formation of an addition salt, such ashydrochloride, toluenesulfonic acid, trifluoroacetic acid and the like.Many of the amino protecting groups are also suitable for protectingcarboxy, hydroxy and mercapto groups. For example, aralkyl groups. Alkylgroups are also sutiable groups for protecting hydroxy and mercaptogroups, such as tert-butyl.

Silyl protecting groups are silicon atoms optionally substituted by oneor more alkyl, aryl and aralkyl groups. Suitable silyl protecting groupsinclude, but are not limited to, trimethylsilyl, triethylsilyl,tri-isopropylsilyl, tert-butyldimethylsilyl, dimethylphenylsilyl,1,2-bis(dimethylsilyl)benzene, 1,2-bis(dimethylsilyl)ethane anddiphenylmethylsilyl. Silylation of an amino groups provide mono- ordi-silylamino groups. Silylation of aminoalcohol compounds can lead to aN,N,O-tri-silyl derivative. Removal of the silyl function from a silylether function is readily accomplished by treatment with, for example, ametal hydroxide or ammonium flouride reagent, either as a discretereaction step or in situ during a reaction with the alcohol group.Suitable silylating agents are, for example, trimethylsilyl chloride,tert-buty-dimethylsilyl chloride, phenyldimethylsilyl chloride,diphenylmethyl silyl chloride or their combination products withimidazole or DMF. Methods for silylation of amines and removal of silylprotecting groups are well known to those skilled in the art. Methods ofpreparation of these amine derivatives from corresponding amino acids,amino acid amides or amino acid esters are also well known to thoseskilled in the art of organic chemistry including amino acid/amino acidester or aminoalcohol chemistry.

Protecting groups are removed under conditions which will not affect theremaining portion of the molecule. These methods are well known in theart and include acid hydrolysis, hydrogenolysis and the like. Apreferred method involves removal of a protecting group, such as removalof a benzyloxycarbonyl group by hydrogenolysis utilizing palladium oncarbon in a suitable solvent system such as an alcohol, acetic acid, andthe like or mixtures thereof. A t-butoxycarbonyl protecting group can beremoved utilizing an inorganic or organic acid, such as HCl ortrifluoroacetic acid, in a suitable solvent system, such as dioxane ormethylene chloride. The resulting amino salt can readily be neutralizedto yield the free amine. Carboxy protecting group, such as methyl,ethyl, benzyl, tert-butyl, 4-methoxyphenylmethyl and the like, can beremoved under hydroylsis and hydrogenolysis conditions well known tothose skilled in the art.

Procedures for preparing the compounds of this invention are set forthbelow. It should be noted that the general procedures are shown as itrelates to preparation of compounds having unspecified stereochemistry.However, such procedures are generally applicable to those compounds ofa specific stereochemistry, e.g., where the stereochemistry about agroup is (S) or (R). In addition, the compounds having onestereochemistry (e.g., (R)) can often be utilized to produce thosehaving opposite stereochemistry (i.e., (S)) using well-known methods,for example, by inversion.

Preparation of Compounds of Formula I

The compounds of the present invention represented by Formula I abovecan be prepared using various synthesis techniques, many of which areincluded by reference. In particular, compounds of the present inventioncan be prepared following the general procedures discussed below.

A general synthesis useful for the preparation of the novel compounds ofthis invention is illustrated in Scheme I, which employs a convergentroute to the azepine ring and larger ring systems. According to thismethod, the readily available Horner-Emmons reagent is reacted understandard conditions (see Wadsworth, Org. Reactions, 1977, 25, 73) withan aldehyde variably substituted by a silyl ether as well as additionalsubstitution on the alkyl chain (R5, R6, R9, R10) to provide the α,βunsaturated ester. Deprotection of the silyl group, activation of thealcohol to provide a leaving group and intramolecular base catalyzedclosure provides a key intermediate. Subsequent deprotection of thet-BOC group with dry HCl/Ethyl acetate (Gibson, J. Org. Chem., 1994, 59,3216) or with TFA and

sulfonylation with a sulfonyl halide in the presence of a base,preferably a hindered amine base such as triethyl amine in a chlorinatedsolvent provides the substituted sulfonamide. The R group is a groupthat can be converted into an amino group using methods well known tothose skilled in the art, such as benzyl amine, silyl protected benzylamine, phthalimide, or other readily available nucleophilic amineequivalents. The protected primary amine is deprotected to theunsubstituted primary amine by methods known in the art for examplehydrogenation in the presence of a metal catalyst. The primary amine isthen funtionalized to provide the ester derivatives of the finalproduct. Methods for funtionalization include sulfonylation as describedabove, treatment with isocyanates to prepare ureas, treatment with acidchlorides or mixed anhydrides to provide amides, reductive aminations toprovide amines, and chloroformates to provide carbamates (See Compendiumof Synthetic Organic Methods, Wiley). These adducts are treated withaqueous alkali bases such as LiOH to provide the free acid products whenmethyl or ethyl esters are used or TFA when the t-butyl ester is used asthe ester component.

A second general synthesis useful for the preparation of the novelcompounds of this invention is illustrated in Scheme II, which employs aconvergent route to the azepine ring.

The readily available aspartic, or glutamic acid derivative is protectedand allylated as described previously for an analog (see Baldwin,Tetrahedron, 1989, 45, 6309 and references cited therein). Mitsunobureaction of the resulting sulfonamide (see Mitsunobu, Synthesis,1981, 1) provides the bis olefin. Treatment of the resulting olefin witha metathesis reagent (see Schuster, Angew. Chem. Int. Ed. Engl. 1997,36, 2036) provides the cyclized olefin. Saponification, as known by oneskilled in the art, followed by curtius rearangment of the resultantacid under known conditions (Tetrahedron, 1974, 30, 2151) provides thedesired carbamates. The t-butyl acid protected carbamates can bedeprotected with concentrated trifluoroacetic acid (TFA) to provide thefinal products. Additionally, by choosing the appropriate alcoholtrapping agent for the Curtius rearangement, for example, 4-methoxybenzyl alcohol, the carbamate may be diferentially deprotected to theamine with dilute (3%) TFA in a chlorinated solvent to provide thet-butyl protected acid, amine salt. Sulfonylation, as describedpreviously, or treatment with the appropiate alkylating or acylatingagent as known by one skilled in the art and deprotection of the t-butylester as described provides the compounds. Larger rings can be formed byusing homologues of allyl-iodide or hydroxy-allyl, such as4-iodo-1-butene, 4-hydroxy-1-butene, 5-iodo-1-pentene,5-hydroxy-1-pentene, 4-iodo-2-butene, 4-hydroxy-2-butene and the like.

Intermediates from Scheme II can be used as starting materials forsubstituents R⁵, R⁶, R⁹ and R¹⁰. For example, the aspartic acidderivative can be alkylated with a variety of polysubstiuted allyliodides or triflates such as CH₂═CH₂CHR⁷R¹⁰I followed by Mitzunubureaction with with allyl and homoallyl alcohols to provide intermediatesfor methathesis reaction. The compounds claimed may also be prepared byfuntionalization of the olefinic intermediates after metathesis. Forexample, the olefin can be hydrogenated under standard conditions,preferably, Pd/C under an atmosphere of hydrogen in a solvent such as aalcohol, or ethyl acetate. The olefin can be hydroborated with a boranereagent,(see Brown, Borane Reagents, Academic Press, New York, 1988)preferably, BH₃-DMS, and the subsequent borane complex oxidized withH₂O₂ to provide the alcohol or with cromium agents under standardconditions (see Hudlicky, Oxidations in Organic Chemistry, ACS mongraph186, 1990), provides the ketone. The ketone can serve as a electrophilwith wittig reagents, organometallic agents or can be reacted withaldehydes under basic or acidic conditions to undergo aldolcondensations. The olefins can undergo allylic oxidation with chromiumor preferably selenium reagents (see Rabjohn, Org. Reactions, 1976, 24,261) as known in the art to provide allylic alcohols which activated asa leaving group and can be substituted with carbon, oxygen, nitrogen orsulphur nucleophiles as known in the art under neutral or basicconditions with or without palladium or lewis acid catalysis. Additionalcompounds can be prepared by treatment of the olefin with a aryl oralkenyl halide or triflate in the presence of a palladium catalyst toundergo a Heck reaction.(for an extensive reveiw of bond formation usingpalladium catalysis see Tsuji, Palladium Reagents and Catalysis, Wiley,1995) The formed olefin can be funtionalized as described above toprovide additional substitution. The olefin can be epoxidized with MCPBAor a related peroxide to for the epoxide that can be substituted in thepresence or absence or a lewis acid with a reactive Carbon, nitrogen,oxygen or sulphur nucleophil as known in the art.

Alternatively, substituted urea derivatives can be prepared by reactingthe isocyanate intermediate formed in the Curtius rearrangement by usingan amine (HNR³¹R³²) in place of the alcohol (R³⁰—OH) (Scheme III).

Further, the carbamate formed in Scheme II can be hydrolyzed in acid tothe free amine (Scheme IV) which can then be derivatized, such as byalkylation, reductive alkylation, sulfonylation, aminosulfonylation,acylated and the like, such as in Scheme V.

It is apparent from the above description that no single generalsynthesis can be used in the preparation of all of the novel compoundsof this invention, because some of the radicals, well known to thoseskilled in the art, will or may have the potential of interfering with,competing with or inhibiting the some of the reactions involved in thepathway. However, one skilled in the art is fully aware of appropriatepoint in the synthetic pathway when a radical may be introduced and whenprotecting groups can be used.

Sulfonyl halides can be prepared by the reaction of a suitable alkyl,aryl, heteroaryl, heterocyclyl and the like Grignard or lithium reagentswith sulfuryl chloride, or sulfur dioxide followed by oxidation with ahalogen, preferably chlorine. Alkyl, heteroaryl, heterocyclyl, aryl andthe like Grignard or lithium reagents can be prepared from theircorresponding halide (such as chloro or bromo) compounds which arecommercially available or readily prepared from commercially availablestarting materials using known methods in the art. Alternatively,mercaptans may be oxidized to sulfonyl chlorides using chlorine in thepresence of water under carefully controlled conditions. Additionally,sulfonic acids may be converted into sulfonyl halides using reagentssuch as PCl₅, SOCl₂, ClC(O)C(O)Cl and the like, and also to anhydridesusing suitable dehydrating reagents. The sulfonic acids are eithercommercially available or may be prepared using procedures well known inthe art from commercially available starting materials. In place of thesulfonyl halides, sulfinyl halides or sulfenyl halides can be utilizedto prepare compounds wherein the sulfonyl moiety is replaced by ansulfinyl or thio moiety, respectively. Arylsulfonic acids, benzo fusedheterocyclyl sulfonic acids or heteroaryl sulfonic acids can be preparedby sulfonation of the aromatic ring by well known methods in the art,such as by reaction with sulfuric acid, SO₃, SO₃ complexes, such asDMF(SO₃), pyridine(SO₃), N,N-dimethylacetamide(SO₃), and the like.Preferably, such sulfonyl halides are prepared from such aromaticcompounds by reaction with DMF(SO₃) and SOCl₂ or ClC(O)C(O)Cl. Thereactions may be performed stepwise or in a single pot.

Additional R1 substitution can be obtained by further reactions on thesulfonamide after reaction of the sulfonyl halide with the relatedamine. For instance, nitro substituted aryl or heteroaryl sulphonamidescan be reduced to the aniline and substituted or converted to thediazonium salt and reacted further to provide the described compounds bymethods known to one skilled in the art. Additional R1 substitutions canbe obtained by reaction of fluorine, halogen, ortrifluoromethanesulfonyloxy substituted aryl or heteroaryl or alkylsulfonyl chlorides with the related amine followed by substitution ofthe reactive intermediate with oxygen, nitrogen, sulfur or carbonnucleophile in the presence or absence of a transition metal catalystsuch as palladium to provide the desired compounds.(For a monograph onthe topic, see Miller, Aromatic Nucleophilic Substitution, Elsevier,N.Y., 1968).

Alkyl sulfonic acids, aryl sulfonic acids, heterocyclyl sulfonic acids,heteroaryl sulfonic acids, alkylmercaptans, arylmercaptans,heterocyclylmercaptans, heteroarylmercaptans, alkylhalides, arylhalides,heterocyclylhalides, heteroarylhalides, and the like are commerciallyavailable or can be readily prepared from starting materialscommercially available using standard methods well known in the art.

Thioether derivatives can be converted into the corresponding sulfone orsulfoxide by oxidizing the thioether derivative with a suitableoxidation agent in a suitable solvent. Suitable oxidation agentsinclude, for example, hydrogen peroxide, sodium meta-perborate, oxone(potassium peroxy monosulfate), meta-chloroperoxy benzoic acid, periodicacid and the like, including mixtures thereof. Suitable solvents includeacetic acid (for sodium meta-perborate) and, for other peracids, etherssuch as THF and dioxane, and acetonitrile, DMF and the like, includingmixtures thereof.

The compounds of the invention may be produced in racemic or opticallypure form. When a single enantiomer is prepared, these may besynthesized by beginning with optically pure starting materials, byresolution of a basic or acidic racemic intermediate with theappropriate chiral acid or base respectivily, as known to one skilled inthe art, or by the addition of a chiral protecting group to the racemicintermediate or final product where the diasteriomeric pair can beseperated by chromatoraphy or crystallization.

The chemical reactions described above are generally disclosed in termsof their broadest application to the preparation of the compounds ofthis invention. Occasionally, the reactions may not be applicable asdescribed to each compound included within the disclosed scope. Thecompounds for which this occurs will be readily recognized by thoseskilled in the art. In all such cases, either the reactions can besuccessfully performed by conventional modifications known to thoseskilled in the art, e.g., by appropriate protection of interferinggroups, by changing to alternative conventional reagents, by routinemodification of reaction conditions, and the like, or other reactionsdisclosed herein or otherwise conventional, will be applicable to thepreparation of the corresponding compounds of this invention. In allpreparative methods, all starting materials are known or readilyprepared from known starting materials.

Prodrugs of the compounds of this invention are also contemplated bythis invention. A prodrug is an active or inactive compound that ismodified chemically through in vivo physicological action, such ashydrolysis, metabolism and the like, into a compound of this inventionfollowing adminstration of the prodrug to a patient. The suitability andtechniques involved in making and using prodrugs are well known by thoseskilled in the art. For a general discussion of prodrugs involvingesters see Svensson and Tunek Drug Metabolism Reviews 165 (1988) andBundgaard Design of Prodrugs, Elsevier (1985). Examples of a maskedcarboxylate anion include a variety of esters, such as alkyl (forexample, methyl, ethyl), cycloalkyl (for example, cyclohexyl), aralkyl(for example, benzyl, p-methoxybenzyl), and alkylcarbonyloxyalkyl (forexample, pivaloyloxymethyl). Amines have been masked asarylcarbonyloxymethyl substituted derivatives which are cleaved byesterases in vivo releasing the free drug and formaldehyde (Bungaard J.Med. Chem. 2503 (1989)). Also, drugs containing an acidic NH group, suchas imidazole, imide, indole and the like, have been masked withN-acyloxymethyl groups (Bundgaard Design of Prodrugs, Elsevier (1985)).Hydroxy groups have been masked as esters and ethers. EP 039,051 (Sloanand Little, Apr. 11, 1981) discloses Mannich-base hydroxamic acidprodrugs, their preparation and use.

Without further elaboration, it is believed that one skilled in the artcan, using the preceding description, utilize the present invention toits fullest extent. The following preferred specific embodiments are,therefore, to be construed as merely illustrative, and not limitative ofthe remainder of the disclosure in any way whatsoever.

All reagents were used as received without purification. All proton andcarbon NMR spectra were obtained on a Bruker nuclear magnetic resonancespectrometer.

The following Examples illustrate the preparation of compounds of thepresent invention and intermediates useful in preparing the compounds ofthe present invention.

EXAMPLE 1

Preparation of1-(4-Methoxy-benzenesulfonyl)-2,3,4,7-tetrahydro-1H-azepine-2,3-dicarboxylicAcid 3-benzyl ester 2-tert-butyl Ester

Step A. 2-Aminosuccinic Acid 4-benzyl Ester 1-tert-butyl Ester

D-Aspartic acid β-benzylester (9 g, 40.3 mmol) is suspended in 75 mlDioxane and 7.5 ml Sulfuric Acid and cooled to −15° C. 2-Methylpropene(75 ml) is added and the reaction mixture is sealed and stirred for 4 hat room temperature. The reaction mixture is then cooled to 0° C. andpoured into 600 ml Diethylether and 325 ml 1M NaOH. The organic phase isseparated and the water phase is extracted twice with 200 mlDiethylether. The combined organic fractions are dried with MgSO₄ for 30min. and filtered. The Diethylether is evaporated and the remaining oilis dried at high vacuum for 24 hours: Cal. 280.2, found (M)⁺ 280.

Step B. 2-(4-Methoxy-benzenesulfonylamino)-succinic Acid 4-benzyl Ester1-tert-butyl Ester

2-Aminosuccinic acid 4-benzyl ester 1-tert-butyl ester (9.57 g, 33.4mmol), Triethylamine (9.3 ml, 66.8 mmol) and4-Methoxybenzenesulfonylchloride (6.9 g, 33.4 mmol) are solved in 50 mlDichloromethane (DCM) and stirred at room temp. for 1 h. The reactionmixture is diluted with 50 ml DCM. 200 ml water are added and theorganic phase is separated. The water phase is extracted twice with DCM.The combined organic extracts are dried with MgSO₄ and filtered. Thesolvent is evaporated and the remaining residue is recrystallized fromDiethylether/Ethylacetate as white needles: ¹H NMR (CDCl₃), ppm: 8.2 Hz,(d, 1H), 7.7 Hz (d, 2H), 7.3 Hz (m, 5H), 7.1 Hz (d, 2H), 5.05 Hz (d,2H), 4.08 Hz (dd, 1H), 3.9 Hz (s, 3H), 2.72 Hz (dd, 1H), 2.59 Hz (dd,1H) 1.21 Hz (s, 9H).

Step C. 2-Allyl-3-(4-methoxy-benzenesulfonylamino)-succinic Acid1-benzyl Ester 4-tert-butyl Ester

100 ml dry Tetrahydrofuran (THF) are cooled to −78° C. 1M THF-solutionof Lithium bis(trimethylsilyl)amide (47.35 ml, 47.35 mmol) are addedwhile the temperature is maintained.2-(4-Methoxy-benzenesulfonylamino)-succinic acid 4-benzyl ester1-tert-butyl ester (10.1 g, 22.5 mmol) are dissolved in 45 ml THF andadded dropwise to the reaction solution. The reaction mixture is allowedto stir for 1 h and then warmed briefly to −40° C. After re-cooling to−78° C. Allyliodide (3.1 ml, 33.8 mmol) dissolved in 30 ml THF are addeddrop-wise. The reaction mixture is allowed to warm to −40° C. and isquenched with a NH₄Cl-solution. The organic phase is separated driedover MgSO₄ and filtered. The solvent is evaporated and the product ispurified with a short flash-chromatography column. Hexane/Ethylacetate(9:1): Cal. 489.6 Found. (M)⁺ 490.

Step D. 2-Allyl-3-[allyl-(4-methoxy-benzenesulfonyl)-amino]-succinicAcid 1-benzyl Ester 4-tert-butyl Ester

Triphenylphosphine (1 g, 3.9 mmol) are solved in 60 ml Tetrahydrofuran(THF) and cooled to 0° C. Diazopropyl dicarboxylate (DIAD) (0.77 ml, 3.9mmol) are added via syringe and the reaction mixture is stirred for 30min. Allyl alcohol (16 μl, 0.23 mmol) is added to the yellow suspensionand then after 10 min.,2-Allyl-3-(4-methoxy-benzenesulfonylamino)-succinic acid 1-benzyl ester4-tert-butyl ester (1.4 g, 2.6 mmol) is added. The reaction mixture isstirred for 30 min. at 0° C. and is then allowed to warm to room temp.After evaporation of most of the THF and flash-chromatography withHexane/Ethylacetate (2:1) the desired product is obtained: ¹H NMR (CDCl₃400 MHz), ppm: 7.80 (d, 2H), 7.38 (m, 5H), 6.95 (d, 2H), 5.75 (m, 2H),5.10 (m, 6H), 3.95 (m, 2H), 3.90 (s, 3H), 3.21 (ddd, 1H), 2.50 (ddd,1H), 2.35 (ddd, 1H), 1.40 (s, 9H).

Step E.1-(4-Methoxy-benzenesulfonyl)-2,3,4,7-tetrahydro-1H-azepine-2,3-dicarboxylicAcid 3-benzyl Ester 2-tert-butyl Ester

2-Allyl-3-[allyl-(4-methoxy-benzenesulfonyl)-amino]-succinic acid1-benzyl ester 4-tert-butyl ester (5.5 g, 10.4 mmol) are solved in 40 mlDichloromethane and deoxygenated and flushed with Argon three times. Thecatalyst (RuCl₂(PCy₃)₂=−Ph) (100 mg, 0.12 mmol) is added and thereaction is deoxygenated and flushed with Argon one more time. Thereaction solution is stirred for 7 h at room temperature. Another (90mg, 0.11 mmol) of the Ruthenium catalyst are added and the reaction isstirred over night. Evaporation of the solvent followed byflash-chromatography, Hexane/Ethylacetate (3:1) afforded the product: 1HNMR (CDCl₃ 400 Mhz), ppm: 7.81 (d, 2H), 7.37 (m, 5H), 6.93 (d, 2H), 5.60(m, 2H), 5.10 (m, 3H), 4.18 (dd, 1H), 4.05 (dd, 1 H), 3.88 (s, 3H), 3.20(ddd, 1H), 2.68 (m, 2H), 1.32 (s, 9H).

EXAMPLE 2

Preparation of1-(4-Methoxy-benzenesulfonyl)-2,3,4,7-tetrahydro-1H-azepine-2,3-dicarboxylicAcid 2-tert-butyl Ester

1-(4-Methoxy-benzenesulfonyl)-2,3,4,7-tetrahydro-1H-azepine-2,3-dicarboxylicacid 3-benzyl ester 2-tert-butyl ester (6 g, 12 mmol) is dissolved in amixture of 120 ml Tetrahydrofuran and 78 ml Water. LiOH·H₂O (1 g, 24mmol) is added. After 45 min., more Water (15 ml) is added and thereaction solution is stirred at room temp. for 24 h. The solvent isevaporated and the remaining solid is resolved in Water/Diethylether.The water layer is acidified to pH 1. The organic phase is separated andthe water phase is extracted twice with Ethylacetate. The combinedorganic fractions are dried with MgSO₄ and filtered. The solvent isevaporated to afford the product: Cal. 412.5, found (M)⁺ 412.1.

EXAMPLE 3

Preparation of 1-(4-Methoxy-benzenesulfonyl)-azepane-2,3-dicarboxylicAcid 2-tert-butyl Ester

1-(4-Methoxy-benzenesulfonyl)-2,3,4,7-tetrahydro-1H-azepine-2,3-dicarboxylicacid 3-benzyl ester 2-tert-butylester (2.28 g, 4.5 mmol) are dissolvedin 40 ml Dioxane/Methanol (3:1). Palladium on charcoal (10%) (170 mg,0.16 mmol) are added under an Argon flow. The flask is evacuated andflushed three times with Hydrogen. The reaction is stirred for 6 h atroom temperature. Filtration through Celite and evaporation of thesolvents afforded the product: ¹H NMR (DMSO, 400 MHz), ppm: 7.81 (d,2H), 6.95 (d, 2H), 5.40 (d, 1H), 3.68 (s, 3H), 3.65 (m, 1H), 3.25 (m,1H), 2.92 (m, 1H), 2.15 (m, 1H), 1.95 (m, 1H), 1.78 (m, 2H) 1.25 (s,9H).

EXAMPLE 4

Preparation of1-(4-Methoxy-benzenesulfonyl)-3-(4-methoxy-benzyloxycarbonyl-amino)-2,3,4,7-tetrahydro-1H-azepine-2-carboxylicAcid tert-butyl Ester

The reaction is performed under an Argon atmosphere and exclusion oflight.1-(4-Methoxy-benzenesulfonyl)-2,3,4,7-tetrahydro-1H-azepine-2,3-dicarboxylicacid 2-tert-butyl ester (550 mg, 1.34 mmol) is dissolved in 7 ml dryTetrahydrofuran (THF). Tripropyl amine (TPA) (280 μl, 1.47 mmol) isadded and the reaction is stirred for 30 minutes at RT. Diphenylphosphoryl azide (318 μl, 1.47 mmol) is added and the reaction isgradually heated to 40° C. for 3 h. The reaction temperature is thenincreased to reflux conditions for 6 h. The reaction mixture is allowedto cool to room temperature and 4-Methoxybenzylalcohol (184 μl, 1.47mmol) is added. The reaction is heated to reflux over night. The solventis evaporated. Flash-chromatography Hexane/Ethylacetate (2:1) affordedthe product: Cal. 383.5 found (M)⁺ 383.0.

EXAMPLE 5

Preparation of3-Benzyloxycarbonylamino-1-(4-methoxy-benzenesulfonyl)-2,3,4,7-tetrahydro-1H-azepine-2-carboxylicAcid

Step A.3-Benzyloxycarbonylamino-1-(4-methoxy-benzenesulfonyl)-2,3,4,7-tetrahydro-1H-azepine-2-carboxylicAcid tert-butyl Ester

The reaction is performed under an Argon athmosphere.1-(4-methoxy-benzenesulfonyl)-2,3,4,7-tetrahydro-1H-azepine-2,3-dicarboxylicacid 2-tert-butyl ester (300 mg, 0.73 mmol) is dissolved in 4 ml Dioxane(dry). Tripropylamine (TPA) (98 μl, 0.73 mmol) is added and the reactionis stirred for 15 minutes at RT. Diphenyl phosphoryl azide (157 μl, 0.73mmol) is added and the reaction is gradually heated to 60° C. for 3 h.The reaction is then allowed to cool to room temperature. Benzyl alcohol(235 μl, 2.2 mmol) is added and the reaction solution is heated to 60°C. over night. The reaction solution is diluted with Ethylacetate andwashed with 2 M Citric Acid and Water. The organic phase is separated,dried with MgSO₄ and filtrated. The solvent is evaporated and theremaining oil is purified by flash-chromatography, Hexane/Ethylacetate(2:1): Cal. 516.6, found (M)⁺ 517.

Step B. 3-Benzyloxycarbonylamino-1-(4-methoxy-benzenesulfonyl)-2,3,4,7-tetrahydro-1H-azepine-2-carboxylic Acid

3-Benzyloxycarbonylamino-1-(4-methoxy-benzenesulfonyl)-2,3,4,7-tetrahydro-1H-azepine-2-carboxylicacid tert-butyl ester (28 mg, 0.054 mmol) is dissolved in 4 mlDichloro-methane/Trifluoroacetic Acid; 3:1 and stirred for 5 h at roomtemperature. The solvent/reagent are evaporated and the remaining oil isco-evaporated from Toluene twice. Flash-chromatography,Hexane/Ethylacetate; 1:1 afforded the desired product: Cal. 460.51,found (M)⁺ 460.9.

EXAMPLE 6

Preparation of3-(3,3-Dibenzylureido)-1-(4-methoxy-benzenesulfonyl)-2,3,4,7-terahydro-1H-azepine-2-carboxylicAcid

Step A.3-(3,3-Dibenzylureido)-1-(4-methoxy-benzenesulfonyl)-2,3,4,7-tetrahydro-1H-azepine-2-carboxylicAcid tert-butyl Ester

The reaction is performed under an Argon blanket.1-(4-Methoxy-benzenesulfonyl)-2,3,4,7-tetrahydro-1H-azepine-2,3-dicarboxylicacid 2-tert-butyl ester (204 mg, 0.5 mmol) is dissolved in 10 ml dryDioxane. Tripropylamine (94 μl, 0.5 mmol) is added and then Diphenylphosphoryl azide (DPPA). The reaction is heated to 75° C. for 5 h. Aftercooling to room temperature, Dibenzylamine (190.6 μl, 1 mmol) is addedvia syringe. The reaction is heated to 70° C. and stirred over night.Evaporation of the solvents and flash-chromatography, Hexane/Ethylacetate (1:1) afforded the product: Cal. 606.8 found (M)⁺ 606.2.

Step B. 3-(3,3-Dibenzylureido)-1-(4-methoxy-benzenesulfonyl)-2,3,4,7-terahydro-1H-azepine-2-carboxylic Acid

3-(3,3-Dibenzylureido)-1-(4-methoxy-benzenesulfonyl)-2,3,4,7-tetrahydro-1H-azepine-2-carboxylicacid tert-butyl ester (200 mg, 0.33 mMol) is reacted in the same manneras3-Benzyloxycarbonylamino-1-(4-methoxy-benzenesulfonyl)-2,3,4,7-tetrahydro-1H-azepine-2-carboxylicacid tert-butyl ester and purified by flash-chromatography,Dichloromethane/Methanol (9:1) to afford the free acid: Cal. 550.6 found(M)⁺=550.

EXAMPLE 7

Preparation of3-Amino-1-(4-methoxy-benzenesulfonyl)-2,3,4,7-tetrahydro-1H-azepine-2-carboxylicAcid tert-butyl Ester

1-(4-Methoxy-benzenesulfonyl)-3-(4-methoxybenzyloxycarbonyl-amino)-2,3,4,7-tetrahydro-1H-azepine-2-carboxylic acidtert-butyl ester (370 mg, 0.71 mMol) is dissolved in Dichloromethane (15ml) containing 3% Trifluoroacetic Acid. The reaction is stirred for 1 hat room temperature. The solvents are evaporated and the remaining oilis co-evaporated twice with Toluene. Flash-chromatographyDichloromethane/Methanol (7:1) to afford the free amine: Cal. 546.6found (M)⁺=547.

EXAMPLE 8

Preparation of1-(4-Methoxy-benzenesulfonyl)-3-(phenylmethanesulfonylamino)-2,3,4,7-tetrahydro-1H-azepine-2-carboxylicAcid

Step A. 1-(4-Methoxy-benzenesulfonyl)-3-(phenylmethanesulfonylamino)-2,3,4,7-tetrahydro-1H-azepine-2-carboxylic Acidtert-butyl Ester

3-Amino-1-1(4-methoxy-benzenesulfonyl)-2,3,4,7-tetrahydro-1H-azepine-2-carboxylicacid tert-butyl ester (38 mg, 0.1 mmol) is dissolved in 3 ml dryDichloromethane. Hünigs Base (42 μl, 0.24 mmol) is added and thenalpha-Toluenesulfonyl chloride (28.4 mg, 0.15 mmol) is added. Thereaction mixture is stirred at room temperature for 4 h. The solvent isevaporated and the remaining oil is purified by Flash-chromatographyHexane/Ethylacetate (2:1): ¹H NMR (CDCl₃ 400 MHz), ppm: 7.75 (d, 2H),7.50 (m, 2H),7.4 (m, 3H) 6.99 (d, 2H), 5.70 (m, 2H), 4.85 (d, 1H), 4.56(d, 1H), 4.35 (dd, 2H), 4.22 (dd, 1H), 4.02 (m, 1H), 3.90 (m, 3H), 3.83(m, 1H),2.50 (m, 1H), 2.30 (m, 1H), 1.30 (s, 9H).

Step B. 1-(4-Methoxy-benzenesulfonyl)-3-(phenylmethanesulfonylamino)-2,3,4,7-tetrahydro-1H-azepine-2-carboxylic Acid

1-(4-Methoxy-benzenesulfonyl)-3-(phenylmethanesulfonylamino)-2,3,4,7-tetrahydro-1H-azepine-2-carboxylic acid tert-butyl ester(29 mg, 0.054 mmol) is reacted in the same manner as3-Benzyloxycarbonylamino-1-(4-methoxy-benzenesulfonyl)-2,3,4,7-tetrahydro-1H-azepine-2-carboxylicacid tert-butyl ester: Cal. 479.5 found (M−H)⁺ 478.6. Cal. 498.6, found(MNH₄)⁺ 498.1; ¹H NMR (DMSO, 400 MHz), ppm: 7.85 (d, 2H), 7.38 (m, 5H)7.01 (d, 2H), 5.5 (m, 2H) 4.45 (d, 2H), 4.30 (d, 2H), 4.15 (m, 2H), 4.00(m, 1H), 3.90 (dd, 1H), 3.83 (s, 3H), 2.18 (m, 2H).

EXAMPLE 9

Preparation of1-(4-Methoxy-benzenesulfonyl)-3-(3-phenylpropionylamino)-2,3,4,7-tetrahydro-1H-azepine-2-carboxylicAcid

Step A.1-(4-Methoxy-benzenesulfonyl)-3-(3-phenyl-propionylamino)-2,3,4,7-tetrahydro-1H-azepine-2-carboxylicAcid tert-butyl Ester

3-Amino-1-(4-methoxy-benzenesulfonyl)-2,3,4,7-tetrahydro-1H-azepine-2-carboxylicacid tert-butyl ester (31 mg, 0.08 mmol) is dissolved in 4 mlDichloromethane and cooled to 0° C. Hünigs Base (34 μl, 0.2 mmol) isadded followed by Hydrocinnamyl chloride (18 μl, 0.12 mmol). Thereaction is stirred 1 h at 0° C. and is then allowed to warm to roomtemperature. The solvents are evaporated and the remaining oil ispurified by flash-chromatography, Dichloro-methane/Methanol (9:1)affording the product: Cal. 513.6 found (M+H)⁺=514.9.

Step B.1-(4-Methoxy-benzenesulfonyl)-3-(3-phenyl-propionylamino)-2,3,4,7-tetrahydro-1H-azepine-2-carboxylicAcid

1-(4-Methoxy-benzenesulfonyl)-3-(3-phenylpropionylamino)-2,3,4,7-tetrahydro-1H-azepine-2-carboxylic acid tert-butyl ester(22 mg, 0.04 mmol) is reacted in the same manner as3-Benzyloxycarbonylamino-1-(4-methoxy-benzenesulfonyl)-2,3,4,7-tetrahydro-1H-azepine-2-carboxylicacid tert-butyl ester and purified by flash-chromatography,Dichloromethane/Methanol (9:1) to afford the acid: Cal. 457.5 found(M−H)⁺ 456.6; ¹H NMR (DMSO, 400 MHz), ppm: 7.78 (d, 2H), 7.28 (m, 2H),7.20 (m, 3H), 7.01 (d, 2H), 5.6 (m, 1H), 5.5 (m, 1H), 4.3 (m, 3H), 4.0(m, 1H), 3.82 (s, 3H), 2.8 (t, 2H), 2.35 (m, 2H), 2.05 (m, 2H).

EXAMPLE 10

Preparation of3-(3-Benzylureido)-1-(4-methoxy-benzenesulfonyl)-2,3,4,7-tetrahydro-1H-azepine-2-carboxylicAcid

Step A.3-(3-Benzylureido)-1-(4-methoxy-benzenesulfonyl)-2,3,4,7-tetrahydro-1H-azepine-2-carboxylicAcid tert-butyl Ester

3-Amino-1-(4-methoxy-benzenesulfonyl)-2,3,4,7-tetrahydro-1H-azepine-2-carboxylicacid tert-butyl ester (33 mg, 0.09 mmol) is solved in 3 ml dry Dioxane.Benzylisocyanate (10.6 μl, 0.086 mmol) is added and the reaction isstirred at room temperature for 1 h. Evaporation of the solvent andflash-chromatography, Dichloromethane/Methanol (7:1) afforded theproduct: Cal. 515.6 found (M)⁺ 515.9.

Step B.3-(3-Benzylureido)-1-(4-methoxy-benzenesulfonyl)-2,3,4,7-tetrahydro-1H-azepine-2-carboxylicAcid

3-(3-Benzylureido)-1-(4-methoxy-benzenesulfonyl)-2,3,4,7-tetrahydro-1H-azepine-2-carboxylicacid tert-butyl ester (25 mg, 0.05 mmol) is reacted in the same manneras3-Benzyloxycarbonylamino-1-(4-methoxy-benzenesulfonyl)-2,3,4,7-tetrahydro-1H-azepine-2-carboxylicacid tert-butyl ester and purified by flash-chromatography,Dichloromethane/Methanol (9:1): Cal. 459.5 found (M−H)⁺ 458.2; ¹H NMR(DMSO, 400 MHz), ppm: 7.79 (d, 2H), 7.30 (m, 2H),7.20 (m, 3H) 7.02 (d,2H), 5.60 (m, 1H), 5.50 (m, 1H) 4.3 (m, 3H), 4.00 (m, 1H), 3.93 (m, 3H),2.81 (t, 2H),2.35 (m, 2H), 2.05 (m, 2H).

EXAMPLE 11

Using the procedures of the above general descriptions and Examples 1-10above, the following compounds were prepared:

1-(4-Methoxy-benzenesulfonyl)-3-(phenylethanesulfonylamino)-1H-azepane-2-carboxylic acid: Cal. 496.6 found (M)⁺ 497;

1-(4-Methoxy-benzenesulfonyl)-3-(2-amino-phenylmethanesulfonylamino)-1H-azepane-2-carboxylic acid: Cal. 497.6 found (M)⁺ 498;

1-(4-Methoxy-benzenesulfonyl)-3-(phenylmethanesulfonylamino)-1H-azepane-2-carboxylic acid: Cal. 482.6 found (M)⁺ 483;

cis-1-(4-Methoxy-benzenesulfonyl)-3-(phenylmethanesulfonylamino)-heptamethyleneimine-2-carboxylic acid: Cal. 496.6 found(M−H)⁺ 495;

trans-1-(4-Methoxy-benzenesulfonyl)-3-(phenylmethanesulfonylamino)-heptamethyleneimine-2-carboxylic acid: Cal. 496.6 found(M−H)⁺ 495;

3-Benzyloxycarbonylamino-1-(4-methoxy-benzenesulfonyl)-1H-azepane-2-carboxylicacid: Cal. 462.52 found (M−H)⁺ 461.2;

1-(4-Methoxy-benzenesulfonyl)-3-(methanesulfonylamino)-2,3,4,7-tetrahydro-1H-azepine-2-carboxylicacid: Cal. 404.5 found (M)⁺ 405;

1-(4-Methoxy-benzenesulfonyl)-3-(phenylsulfonylamino)-2,3,4,7-tetrahydro-1H-azepine-2-carboxylicacid: Cal. 466.6 found (M)⁺ 467;

1-(4-Methoxy-benzenesulfonyl)-3-(2-napthylsulfonylamino)-2,3,4,7-tetrahydro-1H-azepine-2-carboxylic acid: Cal. 516.6 found(M)⁺ 517:

1-(4-Methoxy-benzenesulfonyl)-3-(1-napthylsulfonylamino)-2,3,4,7-tetrahydro-1H-azepine-2-carboxylic acid: Cal. 516.6 found(M)⁺ 517;

1-(4-Chlorophenyl-phenylsulfonyl)-3-(phenylmethanesulfonylamino)-2,3,4,7-tetrahydro-1H-azepine-2-carboxylic acid: Cal.560.6 found (M)⁺ 561;

1-(4-Methoxy-benzenesulfonyl)-3-(4-Chlorophenyl-phenylsulfonylamino)-2,3,4,7-tetrahydro-1H-azepine-2-carboxylicacid: Cal. 577.1 found (M)⁺ 577;

1-(4-Methoxy-benzenesulfonyl)-3-(2-nitrophenyl-methanesulfonylamino)-2,3,4,7-tetrahydro-1H-azepine-2-carboxylicacid: Cal. 525.6 found (M)⁺ 526;

1-(4-Methoxy-benzenesulfonyl)-3-(phenylacroylsulfonylamino)-2,3,4,7-tetrahydro-1H-azepine-2-carboxylic acid: Cal. 492.6 found(M)⁺ 493;

1-(4-Methoxy-benzenesulfonyl)-3-(4-iodophenyl-sulfonylamino)-2,3,4,7-tetrahydro-1H-azepine-2-carboxylicacid: Cal. 592.7 found (M−H)⁺ 593;

1-(4-Methoxy-benzenesulfonyl)-3-(acetylamino)-2,3,4,7-tetrahydro-1H-azepine-2-carboxylicacid: Cal. 368.4 found (M)⁺ 369;

1-(4-Methoxy-benzenesulfonyl)-3-(2-thiophene-2-acetylamino)-2,3,4,7-tetrahydro-1H-azepine-2-carboxylicacid: Cal. 450.5 found (M)⁺ 451;

3-(3-Phenethylureido)-1-(4-methoxy-benzenesulfonyl)-2,3,4,7-tetrahydro-1H-azepine-2-carboxylicacid: Cal. 473.5 found (M)⁺ 474;

3-(3-Methylureido)-1-(4-methoxy-benzenesulfonyl)-2,3,4,7-tetrahydro-1H-azepine-2-carboxylicacid: Cal. 383.4 found (M)⁺ 384;

3-(3-Phenylureido)-1-(4-methoxy-benzenesulfonyl)-2,3,4,7-tetrahydro-1H-azepine-2-carboxylicacid: Cal. 445.5 found (M)⁺ 446;

3-(3,3-Benzylmethylureido)-1-(4-methoxy-benzenesulfonyl)-2,3,4,7-terahydro-1H-azepine-2-carboxylicacid: Cal. 473.5 found (M)⁺ 474;

3-(3,3-Benzylphenylureido)-1-(4-methoxy-benzenesulfonyl)-2,3,4,7-terahydro-1H-azepine-2-carboxylicacid: Cal. 535.6 found (M)⁺ 536;

3-Methoxycarbonylamino-1-(4-methoxy-benzenesulfonyl)-2,3,4,7-tetrahydro-1H-azepine-2-carboxylicacid: Cal. 384.41 found (M)⁺ 385;

3-(4-Trifluoromethylbenzyloxycarbonylamino)-1-(4-methoxy-benzenesulfonyl)-2,3,4,7-tetrahydro-1H-azepine-2-carboxylicacid: Cal. 528.5 found (M)⁺ 529;

3-(4-Chlorobenzyloxycarbonylamino)-1-(4-methoxy-benzenesulfonyl)-2,3,4,7-tetrahydro-1H-azepine-2-carboxylicacid: Cal. 494.9 found (M)⁺ 495;

3-(3,5-Dichlorobenzyloxycarbonylamino)-1-(4-methoxy-benzenesulfonyl)-2,3,4,7-tetrahydro-1H-azepine-2-carboxylicacid: Cal. 529.4 found (M)⁺ 530.

EXAMPLE 12

Using the procedures of the above general descriptions and the aboveexamples, the compounds of Table I can be prepared.

TABLE I

R¹ R⁹ n m R¹¹ 4-ClPh—Ph H 0 1 PhCH2SO2 4-ClPh—Ph OH 0 1 PhCH2SO24-ClPh—Ph OMe 0 2 PhCH2OCO 4-ClPh—Ph Ph 1 1 PhCH2OCO 4-ClPh—Ph PyrCH2 01 PhCH2SO2 4-MeOPh—Ph H 0 1 PhCH2SO2 4-MeOPh—Ph OH 0 1 PhCH2SO24-MeOPh—Ph OMe 0 2 PhCH2OCO 4-MeOPh—Ph Ph 1 1 PhCH2OCO 4-MeOPh—Ph PyrCH20 1 PhCH2SO2 4-Ph-4-piperidine- H 0 1 PhCH2SO2 4-Ph 4-Ph-4-piperidine-OH 0 1 PhCH2SO2 4-Ph 4-Ph-4-piperidine- OMe 0 2 PhCH2OCO 4-Ph4-Ph-4-piperidine- Ph 1 1 PhCH2OCO 4-Ph 4-Ph-4-piperidine- PyrCH2 0 1PhCH2SO2 4-Ph 4-benzoamidoPh H 0 1 PhCH2SO2 4 -benzoamidoPh OH 0 1PhCH2SO2 4-benzoamidoPh OMe 0 2 PhCH2OCO 4-benzoamidoPh Ph 1 1 PhCH2OCO4-benzoamidoPh PyrCH2 0 1 PhCH2SO2 4-pyridyl-oxyPh H 0 1 PhCH2SO24-pyridyl-oxyPh OH 0 1 PhCH2SO2 4-pyridyl-oxyPh OMe 0 2 PhCH2OCO4-pyridyl-oxyPh Ph 1 1 PhCH2OCO 4-pyridyl-oxyPh PyrCH2 0 1 PhCH2SO2

EXAMPLE 13

The following assays are in vitro assays which were used to characterizethe ability of compounds of this invention to inhibit collagenase andstromelysin: Human Neutrophil Collagenase Assay and Human FibroblastStromelysin Assay.

Human Neutrophil Collagenase Assay

Human neutrophil collagenase (HNC) activity is determined by usingfluorogenic peptide substrateDnp-Pro-b-Cyclohexyl-Ala-Gly-Cys(Me)-His-Ala-Lys-(N-methylanthranilicacid)-NH₂. The N-terminus Dnp group and the C-terminusN-methyl-anthranilyl moiety (Nma) are fluorescence self-quenching untilthe peptide is cleaved at the Gly-Cys(me) bond. The fluorescence fromthe cleavage products is measured on a Bio-Tek Instrument FL500fluorescence micro-plate reader (excitation at 360 nm, emission at 460nm). The assay is performed in a 96-well plate (in duplicate), and theKm=51 nM for the substrate, and Ki=722 nM for Actinonin have beendetermined. The test compounds (at 100, 33 & 10 mm) are compared fortheir inhibition of HNC activity on the substrate against the activityof Actinonin and Ki's were determined on selected compounds.

Human Fibroblast Stromelysin Assay

Human fibroblast stromelysin (HFS) activity is determined by usingfluorogenic peptide substrateDnp-Pro-b-Cyclohexyl-Ala-Gly-Cys(Me)-His-Ala-Lys-(N-methylanthranilicacid)-NH₂. The N-terminus Dnp group and the C-terminusN-methyl-anthranilyl moiety (Nma) are fluorescence self-quenching untilthe peptide is cleaved at the Gly-Cys(me) bond. The fluorescence fromthe cleavage products is measured on a Bio-Tek Instrument FL500fluorescence micro-plate reader (excitation at 360 nm, emission at 460nm). The assay is performed in a 96-well plate (in duplicate), and theKm=51 nM for the substrate, and Ki=722 nM for Actinonin (an inhibitor ofenzyme activity; Sigma Chemical, St. Louis, Mo.; A6671) have beendetermined as the standard control. The test compounds (at 100, 33 & 10mM) are compared for their inhibition of HFS activity on the substrateagainst the activity of Actinonin and Ki's were determined on selectedcompounds.

The following compounds had a HNC and/or HFS inhibition activity IC₅₀ ofless than 10 μM:

1-(4-Methoxy-benzenesulfonyl)-3-(2-amino-phenylmethanesulfonylamino)-1H-azepane-2-carboxylic acid;

1-(4-Methoxy-benzenesulfonyl)-3-(phenylmethanesulfonylamino)-1H-azepane-2-carboxylic acid;

1-(4-Chlorophenyl-phenylsulfonyl)-3-(phenylmethanesulfonylamino)-2,3,4,7-tetrahydro-1H-azepine-2-carboxylic acid;

1-(4-Methoxy-benzenesulfonyl)-3-(2-nitrophenyl-methanesulfonylamino)-2,3,4,7-tetrahydro-1H-azepine-2-carboxylicacid;

1-(4-Methoxy-benzenesulfonyl)-3-(phenylacroylsulfonylamino)-2,3,4,7-tetrahydro-1H-azepine-2-carboxylic acid;

3-(4-Chlorobenzyloxycarbonylamino)-1-(4-methoxy-benzenesulfonyl)-2,3,4,7-tetrahydro-1H-azepine-2-carboxylicacid;

3-(3,5-Dichlorobenzyloxycarbonylamino)-1-(4-methoxy-benzenesulfonyl)-2,3,4,7-tetrahydro-1H-azepine-2-carboxylicacid.

Methods of Treatment

All of the compounds of this invention are useful in the prophylaxis andtreatment of disease states in which HNC and/or HFS and/or gelatinasesplay a role. Preferably, the compounds of this invention are useful inthe prophylaxis and treatment of rheumatoid arthritis; osteoarthritis;osteopenias (e.g., osteoporosis); periodontitis; gingivitis; corneal,epidermal and gastric ulceration; and tumour metastasis, invasion andgrowth; in neuroinflammatory disorders, such as myelin degradation(e.g., multiple sclerosis); and in angiogenesis dependent diseases, suchas arthritic conditions; cancer; solid tumor growth; psoriasis;proliferative retinopathies; neovascular glaucoma; ocular tumours;angiofibromas; hemangiomas; nephritis; pulmonary inflammation; andrestenosis.

The present invention provides a method of treating a disease state inwhich HNC and/or HFS and/or gelatinases levels are elevated whichcomprises administering an effective amount of a compound of thisinvention. Compounds of this invention are of use in the prophylaxis andacute or chronic therapy of any disease state in a human, or othermammal, which may contribute to the onset or etiology of, is exacerbatedby or mediated by elevated or unregulated HNC and/or HFS and/orgelatinase by mammal's cells. More preferably, this invention relates toa method of lowering the activity levels of HNC and/or HFS and/orgelatinases in a mammal in need thereof which comprises administering aneffective dose of a compound of this invention or a pharmaceuticalcomposition thereof.

A compound of this invention or a pharmaceutical composition thereof isuseful in the treatment or prophylaxis of a number of disease statesincluding rheumatoid arthritis; osteoarthritis; osteopenias (e.g.,osteoporosis); periodontitis; gingivitis; corneal, epidermal and gastriculceration; and tumour metastasis, invasion and growth; inneuroinflammatory disorders, such as myelin degradation (e.g., multiplesclerosis); and in angiogenesis dependent diseases, such as arthriticconditions; cancer; solid tumor growth; psoriasis; proliferativeretinopathies; neovascular glaucoma; ocular tumours; angiofibromas;hemangiomas; nephritis; pulmonary inflammation; and restenosis.

Pharmaceutical Compositions

This invention further relates to the use of a compound of thisinvention in the manufacture of a medicament for the prophylaxis andtreatment, either acutely or chronically, of disease states in which HNCand/or HFS and/or gelatinases play a role.

This invention also relates to a pharmaceutical composition comprising acompound of this invention and a pharmaceutically acceptable carrier,and if desired other active ingredients. The compounds of this inventionare administered by any suitable route, preferably in the form of apharmaceutical composition adapted to such a route, and in a doseeffective for the treatment intended. Therapeutically effective doses ofthe compounds of the present invention required to arrest the progressor prevent tissue damage associated with the disease are readilyascertained by one of ordinary skill in the art.

For the prophylaxis and treatment of disease states, the compounds ofthe present invention may be administered orally, parentally, or byinhalation spray, rectally, or topically in dosage unit formulationscontaining conventional pharmaceutically acceptable carriers, adjuvantsand vehicles. The term parenteral as used herein includes, subcutaneous,intravenous, intramuscular, intrasternal, infusion techniques orintraperitoneally.

The amount of active ingredient that may be combined with the carriermaterials to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration.

The dosage regimen for treating a disease state with the compounds ofthis invention and/or compositions of this invention is based on avariety of factors, including the type of disease, the age, weight, sexand medical condition of the patient, the severity of the condition, theroute of administration, pharmacological considerations such as theactivity, efficacy, pharmacokinetic and toxicology profiles of theparticular compound employed, whether a drug delivery system is utilizedand whether the compound is administered as part of a drug combination.Thus the dosage regimen may vary widely. Dosage levels of the order fromabout 0.01 mg to 80 mg per kilogram of body weight per day, preferablyfrom about 0.5 mg to 30 mg/kg, more preferably from about 1 mg to 15mg/kg are useful for all methods of use disclosed herein. Thepharmaceutically active compounds of this invention can be processed inaccordance with convential methods of pharmacy to produce medicinalagents for administration to patients, mammals including humans.

For oral administration, the pharmaceutical composition may be in theform of, for example, a capsule, a tablet, a suspension, or liquid. Thepharmaceutical composition is preferably made in the form of a dosageunit containing a given amount of the active ingredient. For example,these may contain an amount of active ingredient from about 1 to 250 mg,preferably from about 25 to 150 mg. A suitable daily dose for a human orother mammal may vary widely depending on the condition of the patientand other factors.

The compounds of this invention may also be administered by injection asa composition with suitable carriers including saline, dextrose, orwater. The daily parenteral dosage regimen wll be from about 0.1 toabout 80 mg/kg of total body weight, preferably from about 0.5 to about30 mg/kg, and more preferably from about 1 mg to 15 mg/kg.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectable solutionor suspension in a nontoxic parenterally acceptable diluent or solvent,for example, as a solution in 1,3-butanediol. Among the acceptablevehicles and solvents that may be employed are water, Ringer's solution,and isotonic sodium chloride solution. In addition, sterile, fixed oilsare conventionally employed as a solvent or suspending medium. For thispurpose any bland fixed oil may be employed including synthetic mono- ordiglycerides. In addition, fatty acids such as oleic acid find use inthe preparation of injectables.

Suppositories for rectal administration of the drug can be prepared bymixing the drug with a suitable nonirritating excipient such as cocoabutter and polyethylene glycols which are solid at ordinary temperaturesbut liquid at the rectal temperature and will therefore melt in therectum and release the drug.

A suitable topical dose of compounds of this invention is 0.1 mg to 150mg administered one to four, preferably two or three times daily. Fortopical administration, the active ingredient may comprise from 0.001%to 10% w/w, e.g. from 1% to 2% by weight of the formulation, although itmay comprise as much as 10% w/w, but preferably not more than 5% w/w,and more preferably from 0.1% to 1% of the formulation. Formulationssuitable for topical administration include liquid or semi-liquidpeparations suitable for penetration through the skin such as liniments,lotions, ointments, creams, or pastes and drops suitable foradministration to the eye, ear, or nose.

For administration, the compounds of this invention are ordinarilycombined with one or more adjuvants appropriate for the indicated routeof administration. The compounds may be admixed with lactose, sucrose,starch powder, cellulose esters of alkanoic acids, stearic acid, talc,magnesium stearate, sodium, magnesium oxide, sodium and calcium salts ofphosphoric and sulphuric acids, acacia, gelatin, sodium alginate,polyvinylpyrrolidine, and/or polyvinyl alcohol, and tableted orencapsulated for conventional administration. Alternatively, thecompounds of this invention may be dissolved in saline, water,polyethylene glycol, propylene glycol, ethanol, corn oil, peanut oil,cottonseed oil, sesame oil, benzyl alcohol, and/or various buffers.Other adjuvants and modes of administration are well known in thepharmaceutical art. The carrier or diluent may include time delaymaterial, such as glyceryl monostearate or glyceryl distearate alone orwith a wax, or other materials well known in the art.

The pharmaceutical compositions may be made up in a solid form includinggranules, powders or suppositories or in a liquid form such assolutions, suspensions, or emulsions. The pharmaceutical compositionsmay be subjected to conventional pharmaceutical operations such assterilization and/or may contain conventional adjuvants, such aspreservatives, stabilizers, wetting agents, emulsifiers, buffers, etc.

Solid dosage forms for oral administration may include capsules,tablets, pills, powders, and granules. In such solid dosage forms, theactive compound may be admixed with at least one inert diluent such assucrose lactose or starch. Such dosage forms may also comprise, as innormal practice, additional substances other than inert diluents, e.g.,lubricating agents such as magnesium stearate. In the case of capsules,tablets, and pills, the dosage forms may also comprise buffering agents.Tablets and pills can additionally be prepared with enteric coatings.

Liquid dosage forms for oral administration may include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups, and elixirscontaining inert diluents commonly used in the art, such as water. Suchcompositions may also comprise adjuvants, such as wetting agents,emulsifying and suspending agents, and sweetening, flavoring, andperfuming agents.

Compounds of the present invention can possess one or more asymmetriccarbon atoms and are thus capable of existing in the form of opticalisomers as well as in the form of racemic or nonracemic mixturesthereof. The optical isomers can be obtained by resolution of theracemic mixtures according to conventional processes, for example byformation of diastereoisomeric salts by treatment with an opticallyactive acid or base. Examples of appropriate acids are tartaric,diacetyltartaric, dibenzoyltartaric, ditoluoyltartaric andcamphorsulfonic acid and then separation of the mixture ofdiastereoisomers by crystallization followed by liberation of theoptically active bases from these salts. A different process forseparation of optical isomers involves the use of a chiralchromatography column optimally chosen to maximize the separation of theenantiomers. Still another available method involves synthesis ofcovalent diastereoisomeric molecules by reacting compounds of Formula Iwith an optically pure acid in an activated form or an optically pureisocyanate. The synthesized diastereoisomers can be separated byconventional means such as chromatography, distillation, crystallizationor sublimation, and then hydrolyzed to deliver the enantiomerically purecompound. The optically active compounds of Formula I can likewise beobtained by utilizing optically active starting materials. These isomersmay be in the form of a free acid, a free base, an ester or a salt.

The compounds of the present invention can be used in the form of saltsderived from inorganic or organic acids. These salts include but are notlimited to the following: acetate, adipate, alginate, citrate,aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate,camphorsulfonate, digluconate, cyclopentanepropionate, dodecylsulfate,ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulfate,heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide,hydroiodide, 2-hydroxy-ethanesulfonate, lactate, maleate,methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmoate,pectinate, persulfate, 3-phenylpropionate, picrate, pivalate,propionate, succinate, tartrate, thiocyanate, tosylate, mesylate andundecanoate. Also, the basic nitrogen-containing groups can bequaternized with such agents as lower alkyl halides, such as methyl,ethyl, propyl, and butyl chloride, bromides, and iodides; dialkylsulfates like dimethyl, diethyl, dibutyl, and diamyl sulfates, longchain halides such as decyl, lauryl, myristyl and stearyl chlorides,bromides and iodides, aralkyl halides like benzyl and phenethylbromides, and others. Water or oil-soluble or dispersible products arethereby obtained.

Examples of acids which may be employed to form pharmaceuticallyacceptable acid addition salts include such inorganic acids ashydrochloric acid, sulphuric acid and phosphoric acid and such organicacids as oxalic acid, maleic acid, succinic acid and citric acid. Otherexamples include salts with alkali metals or alkaline earth metals, suchas sodium, potassium, calcium or magnesium or with organic bases.

While the compounds of the invention can be administered as the soleactive pharmaceutical agent, they can also be used in combination withone or more other agents. When administered as a combination, thetherapeutic agents can be formulated as separate compositions which aregiven at the same time or different times, or the therapeutic agents canbe given as a single composition.

The foregoing is merely illustrative of the invention and is notintended to limit the invention to the disclosed compounds. Variationsand changes which are obvious to one skilled in the art are intended tobe within the scope and nature of the invention which are defined in theappended claims.

From the foregoing description, one skilled in the art can easilyascertain the essential characteristics of this invention, and withoutdeparting from the spirit and scope thereof, can make various changesand modifications of the invention to adapt it to various usages andconditions.

What is claimed is:
 1. A compound of formula

or a pharmaceutically acceptable salt thereof, wherein m is 1; and n is0; R¹ is (1) an alkyl, alkenyl, alkynyl, cycloalkyl or heterocyclylradical optionally substituted by 1-3 radicals of —OH, —OR³, —SR³,—S(O)R³, —S(O)₂R³, —C(O)R³, —NR³R⁴, aryl, heteroaryl, cycloalkyl orheterocyclyl; or (2) an aryl radical optionally substituted by anoptionally substituted monocyclic heteroaryl or heterocyclyl radical of5-6 ring members which is optionally substituted by a phenyl radical ormonocyclic heteroaryl radical of 5-6 ring members; or (3) a heteroarylradical optionally substituted by an optionally substituted phenyl or amonocyclic heteroaryl or heterocyclyl radical of 5-6 ring members whichis optionally substituted by a phenyl radical or monocyclic heteroarylradical of 5-6 ring members; wherein the phenyl, aryl, heteroaryl,cycloalkyl and heterocyclyl radicals of (1), (2) and (3) are optionallysubstituted by 1-3 radicals of hydroxy, —OR³, —SR³, —S(O)R³, —S(O)₂R³,—C(O)R³, —NR³R⁴, amino, alkanoylamino, alkylsulfonylamino,alkoxycarbonylamino, alkoxycarbonyl, cyano, halo, azido, alkyl orhaloalkyl; provided that the total number of phenyl, aryl, heteroaryl,cycloalkyl and heterocyclyl radicals in R¹ is 0-3; wherein each R³ isindependently an alkyl, haloalkyl, aryl, heteroaryl, aryl-alkyl orheteroaryl-alkyl radical, wherein the aryl and heteroaryl radicals areoptionally substituted by 1-3 radicals of hydroxy, alkoxy, alkylthiol,amino, alkanoylamino, alkylsulfonylamino, alkylsulfinyl, alkylsulfonyl,alkoxycarbonylamino, alkoxycarbonyl, cyano, halo, azido, alkyl,haloalkyl or haloalkoxy; and each R⁴ is independently a hydrogen oralkyl radical; R¹¹ is a —C(O)—R³¹, —C(O)—OR³⁰, —C(O)—NR³²R³¹, —S(O)₂—R³⁰or —S(O)₂—NR³²R³¹ radical; R⁵ and R⁶ are each independently a hydrogenor alkyl radical; or CR⁵—CR⁶ is C═C; wherein R⁹ and R¹⁰ are eachindependently —B-A, provided that the combined total number of aryl,heteroaryl, cycloalkyl and heterocyclyl radicals in R⁹, R¹⁰ and R¹¹ is0-3; wherein each B is independently a (1) bond; (2) alkyl, alkenyl oralkynyl radical optionally substituted by (a) 1-3 radicals of amino,alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino,alkylsulfonylamino, hydroxy, alkoxy, alkylthio, cyano or halo, and/or(b) 1-2 radicals of heterocyclyl, aryl or heteroaryl optionallysubstituted by 1-3 radicals of amino, alkylamino, dialkylamino,alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy,alkylthio, cyano, halo, alkyl, haloalkyl or haloalkoxy; (3) heterocyclylradical optionally substituted by 1-3 radicals of amino, alkylamino,dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino,hydroxy, alkoxy, alkylthio, cyano, alkyl, haloalkyl or haloalkoxy; or(4) aryl or heteroaryl radical optionally substituted by 1-3 radicals ofamino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino,alkylsulfonylamino, hydroxy, alkoxy, alkylthio, cyano, halo, alkyl,haloalkyl or haloalkoxy; each A is independently a (1) hydrogen radical;(2) halo, cyano or nitro radical (3) —C(O)—R³⁰, —C(O)—OR³¹,—C(O)—NR³²R³¹ or —C(NR³²)—NR³²R³¹ radical; (4) —OR³¹, —O—C(O)—R³¹,—O—C(O)—NR³²R³¹ or —O—C(O)—NR³³—S(O)₂—R³⁰ radical; (5) —SR³¹, —S(O)—R³⁰,—S(O)₂—R³⁰, —S(O)₂—NR³²R³¹, —S(O)₂—NR³³—C(O)—R³¹, —S(O)₂—NR³³—C(O)—OR³⁰or —S(O)₂—NR³³—C(O)—NR³²R³¹ radical; or (6) —NR³²R³¹, —NR³³—C(O)—R³¹,—NR³³—C(O)—OR³⁰, —NR³³—C(O)—NR³²R³¹, —NR³³—C(NR³²)—NR³²R³¹,—NR³³—S(O)₂—R³⁰ or —NR³³—S(O)₂—NR³²R³¹ radical; wherein each R³⁰ isindependently (1) alkyl, alkenyl or alkynyl radical optionallysubstituted by 1-3 radicals of —CO₂R³⁴, amino, alkylamino, dialkylamino,alkanoylamino, alkoxycarbonylamino, N-(alkoxycarbonyl)-N-(alkyl)amino,aminocarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio,alkylsulfinyl, alkylsulfonyl, cyano, halo or aralkoxy, arylalkylthio,arylalkylsulfonyl, cycloalkyl, heterocyclyl, aryl or heteroarylradicals, wherein the cycloalkyl, heterocyclyl, aryl and heteroarylradicals are optionally substituted by 1-3 radicals of amino,alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino,alkylsulfonylamino, alkanoyl, alkoxycarbonyl, hydroxy, alkoxy,alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, halo, alkyl, haloalkylor haloalkoxy; (2) heterocyclyl radical optionally substituted by 1-3radicals of amino, alkylamino, dialkylamino, alkanoylamino,alkoxycarbonylamino, alkylsulfonylamino, alkoxycarbonyl, hydroxy,alkoxy, alkylthio, cyano, alkyl, haloalkyl or haloalkoxy; or (3) aryl orheteroaryl radical optionally substituted by 1-3 radicals of amino,alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino,alkylsulfonylamino, alkoxycarbonyl, hydroxy, alkoxy, alkylthio, cyano,halo, azido, alkyl, haloalkyl or haloalkoxy; each R³¹ is independentlyhydrogen radical or R³⁰; wherein each R³² is independently (1) hydrogenradical; (2) alkyl, alkenyl or alkynyl radical optionally substituted by1-3 radicals of amino, alkylamino, dialkylamino, hydroxy, alkoxy,alkylthio, cyano or halo; or (3) aryl, heteroaryl, arylalkyl,heteroarylalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl orcycloalkylalkyl radicals optionally substituted by 1-3 radicals ofamino, alkylamino, dialkylamino, hydroxy, alkoxy, alkylthio, cyano,alkyl, haloalkyl or haloalkoxy; and each R³³ is independently (1)hydrogen radical; (2) alkyl radical optionally substituted by a radicalof heterocyclyl, aryl or heteroaryl which is optionally substituted by1-3 radicals of amino, alkylamino, dialkylamino, alkanoylamino,alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio,alkylsulfinyl, alkylsulfonyl, cyano, halo, alkyl, haloalkyl orhaloalkoxy; or (3) heterocyclyl, aryl or heteroaryl radical optionallysubstituted by 1-3 radicals of amino, alkylamino, dialkylamino,alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy,alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, halo, alkyl, haloalkylor haloalkoxy; and each R³⁴ is independently hydrogen, alkyl, aryl,heteroaryl, arylalkyl or heteroarylalkyl radical, wherein the aryl andheteroaryl radicals are optionally substituted by 1-3 radicals of amino,alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino,alkylsulfonylamino, hydroxy, alkoxy, alkylthio, alkylsulfinylalkylsulfonyl, cyano, halo, alkyl, haloalkyl or haloalkoxy.
 2. Thecompound of claim 1 or a pharmaceutically acceptable salt thereof,wherein R¹ is (1) an C₁-C₁₂ alkyl, C₂-C₁₂ alkenyl, C₂-C₁₂ alkynyl,cycloalkyl or heterocyclyl radical optionally substituted by 1-3radicals of —OH, —OR³, —SR³, —S(O)R³, —S(O)₂R³, —C(O)R³, —NR³R⁴, aryl,heteroaryl, cycloalkyl or heterocyclyl; or (2) an aryl radicaloptionally substituted by an optionally substituted monocyclicheteroaryl or heterocyclyl radical of 5-6 ring members which isoptionally substituted by a phenyl radical or monocyclic heteroarylradical of 5-6 ring members; or (3) a heteroaryl radical optionallysubstituted by an optionally substituted phenyl or a monocyclicheteroaryl or heterocyclyl radical of 5-6 ring members which isoptionally substituted by a phenyl radical or monocyclic heteroarylradical of 5-6 ring members; wherein the phenyl, aryl, heteroaryl,cycloalkyl and heterocyclyl radicals of (1), (2) and (3) are optionallysubstituted by 1-3 radicals of hydroxy, —OR³, —SR³, —S(O)R³, —S(O)₂R³,—C(O)R³, —NR³R⁴, amino, C₁-C₈ alkanoylamino, C₁-C₈ alkylsulfonylamino,C₁-C₈ alkoxycarbonylamino, C₁-C₈ alkoxycarbonyl, cyano, halo, azido,C₁-C₈ alkyl or C₁-C₈ haloalkyl of 1-3 halo radicals; provided that thetotal number of phenyl, aryl, heteroaryl, cycloalkyl and heterocyclylradicals in R¹ is 0-3; wherein each R³ is independently a C₁-C₈ alkyl,C₁-C₈ haloalkyl of 1-3 halo radicals, aryl, heteroaryl, aryl-C₁-C₄-alkylor heteroaryl-C₁-C₄-alkyl radical, wherein the aryl and heteroarylradicals are optionally substituted by 1-3 radicals of hydroxy, C₁-C₄alkoxy, C₁-C₄ alkylthiol, amino, C₁-C₈ alkanoylamino, C₁-C₈alkylsulfonylamino, C₁-C₄ alkylsulfinyl, C₁-C₄ alkylsulfonyl, C₁-C₈alkoxycarbonylamino, C₁-C₈ alkoxycarbonyl, cyano, halo, azido, C₁-C₈alkyl, C₁-C₈ haloalkyl of 1-3 halo radicals or C₁-C₈ haloalkoxy of 1-3halo radicals; and each R⁴ is independently a hydrogen or C₁-C₈ alkylradical; R¹¹ is a —C(O)—R³¹, —C(O)—OR³⁰, —C(O)—NR³²R³¹, —S(O)₂—R³⁰ or—S(O)₂—NR³²R³¹ radical; R⁵ and R⁶ are each independently a hydrogen orC₁-C₄ alkyl radical; or CR⁵-CR⁶ is C═C; wherein R⁹ and R¹⁰ are eachindependently —B-A, provided that the combined total number of aryl,heteroaryl, cycloalkyl and heterocyclyl radicals in R⁹, R¹⁰ and R¹¹ is0-3; wherein each B is independently a (1) bond; (2) C₁-C₈ alkyl, C₂-C₈alkenyl or C₂-C₈ alkynyl radical optionally substituted by (a) 1-3radicals of amino, C₁-C₄ alkylamino, di-(C₁-C₄ alkyl)amino, C₁-C₅alkanoylamino, (C₁-C₄ alkoxy)carbonylamino, C₁-C₄ alkylsulfonylamino,hydroxy, C₁-C₄ alkoxy, C₁-C₄ alkylthio, cyano or halo, and/or (b) 1-2radicals of heterocyclyl, aryl or heteroaryl optionally substituted by1-3 radicals of amino, C₁-C₄ alkylamino, di-(C₁-C₄ alkyl)amino, C₁-C₅alkanoylamino, (C₁-C₄ alkoxy)carbonylamino, C₁-C₄ alkylsulfonylamino,hydroxy, C₁-C₄ alkoxy, C₁-C₄ alkylthio, cyano, halo, C₁-C₄ alkyl, C₁-C₄haloalkyl of 1-3 halo radicals or C₁-C₄ haloalkoxy of 1-3 halo radicals;(3) heterocyclyl radical optionally substituted by 1-3 radicals ofamino, C₁-C₄ alkylamino, di-(C₁-C₄ alkyl)amino, C₁-C₅ alkanoylamino,(C₁-C₄ alkoxy)carbonylamino, C₁-C₄ alkylsulfonylamino, hydroxy, C₁-C₄alkoxy, C₁-C₄ alkylthio, cyano, C₁-C₄ alkyl, C₁-C₄ haloalkyl of 1-3 haloradicals or C₁-C₄ haloalkoxy of 1-3 halo radicals; or (4) aryl orheteroaryl radical optionally substituted by 1-3 radicals of amino,C₁-C₄ alkylamino, di-(C₁-C₄ alkyl)amino, C₁-C₅ alkanoylamino, (C₁-C₄alkoxy)carbonylamino, C₁-C₄ alkylsulfonylamino, hydroxy, C₁-C₄ alkoxy,C₁-C₄ alkylthio, cyano, halo, C₁-C₄ alkyl, C₁-C₈ haloalkyl of 1-3 haloradicals or C₁-C₈ haloalkoxy of 1-3 halo radicals; each A isindependently a (1) hydrogen radical; (2) halo, cyano or nitro radical;(3) —C(O)—R³⁰, —C(O)—OR³¹, —C(O)—NR³²R³¹ or —C(NR³²)—NR³²R³¹ radical;(4) —OR³¹, —O—C(O)—R³¹, —O—C(O)—NR³²R³¹ or —O—C(O)—NR³³—S(O)₂—R³⁰radical; (5) —SR³¹, —S(O)—R³⁰, —S(O)₂—R³⁰, —S(O)₂—NR³²R³¹,—S(O)₂—NR³³—C(O)—R³¹, —S(O)₂—NR³³—C(O)—OR³⁰ or —S(O)₂—NR³³—C(O)—NR³²R³¹radical; or (6) —NR³²R³¹, —NR³³—C(O)—R³¹, —NR³³—C(O)—OR³⁰,NR³³—C(O)—NR³²R³¹, —NR³³—C(NR³²)—NR³²R³¹, —NR³³—S(O)₂—R³⁰ or—NR³³—S(O)₂—NR³²R³¹ radical; wherein each R³⁰ is independently (1) C₁-C₈alkyl, C₂-C₈ alkenyl or C₂-C₈ alkynyl radical optionally substituted by1-3 radicals of —CO₂R³⁴, amino, C₁-C₄ alkylamino, di-(C₁-C₄ alkyl)amino,C₁-C₅ alkanoylamino, (C₁-C₄ alkoxy)carbonylamino, N-((C₁-C₄alkoxy)carbonyl)-N-(C₁-C₄ alkyl)amino, aminocarbonylamino, C₁-C₄alkylsulfonylamino, hydroxy, C₁-C₄ alkoxy, C₁-C₄ alkylthio, C₁-C₄alkylsulfinyl, C₁-C₄ alkylsulfonyl, cyano, halo, aryl-C₁-C₄-alkoxy,aryl-C₁-C₄-alkylthio, aryl-C₁-C₄-alkylsulfonyl, C₃-C₈ cycloalkyl,heterocyclyl, aryl or heteroaryl radicals, wherein the cycloalkyl,heterocyclyl, aryl and heteroaryl radicals are optionally substituted by1-3 radicals of amino, C₁-C₄ alkylamino, di-(C₁-C₄ alkyl)amino, C₁-C₅alkanoylamino, (C₁-C₄ alkoxy)carbonylamino, C₁-C₄ alkylsulfonylamino,C₁-C₅ alkanoyl, (C₁-C₄ alkoxy)carbonyl, hydroxy, C₁-C₄ alkoxy, C₁-C₄alkylthio, C₁-C₄ alkylsulfinyl, C₁-C₄ alkylsulfonyl, cyano, halo, C₁-C₄alkyl, C₁-C₄ haloalkyl of 1-3 halo radicals or C₁-C₄ haloalkoxy of 1-3halo radicals; (2) heterocyclyl radical optionally substituted by 1-3radicals of amino, C₁-C₄ alkylamino, di-(C₁-C₄ alkyl)amino, C₁-C₅alkanoylamino, (C₁-C₄ alkoxy)carbonylamino, C₁-C₄ alkylsulfonylamino,(C₁-C₄ alkoxy)carbonyl, hydroxy, C₁-C₄ alkoxy, C₁-C₄ alkylthio, cyano,C₁-C₄ alkyl, C₁-C₄ haloalkyl of 1-3 halo radicals or C₁-C₄ haloalkoxy of1-3 halo radicals; or (3) aryl or heteroaryl radical optionallysubstituted by 1-3 radicals of amino, C₁-C₄ alkylamino, di-(C₁-C₄alkyl)amino, C₁-C₅ alkanoylamino, (C₁-C₄ alkoxy)carbonylamino, C₁-C₄alkylsulfonylamino, (C₁-C₄ alkoxy)carbonyl, hydroxy, C₁-C₄ alkoxy, C₁-C₄alkylthio, cyano, halo, azido, C₁-C₄ alkyl, C₁-C₄ haloalkyl of 1-3 haloradicals or C₁-C₄ haloalkoxy of 1-3 halo radicals; each R³¹ isindependently hydrogen radical or R³⁰; wherein each R³² is independently(1) hydrogen radical; (2) C₁-C₈ alkyl, C₂-C₈ alkenyl or C₂-C₈ alkynylradical optionally substituted by 1-3 radicals of amino, C₁-C₄alkylamino, di-(C₁-C₄-alkyl)amino, hydroxy, C₁-C₄ alkoxy, C₁-C₄alkylthio, cyano or halo; or (3) aryl, heteroaryl, aryl-C₁-C₄-alkyl,heteroaryl-C₁-C₄-alkyl, heterocyclyl, heterocyclyl-C₁-C₄-alkyl, C₃-C₈cycloalkyl or C₃-C₈-Cycloalkyl-C₁-C₄-alkyl radical optionallysubstituted by 1-3 radicals of amino, C₁-C₄ alkylamino,di-(C₁-C₄-alkyl)amino, hydroxy, C₁-C₄ alkoxy, C₁-C₄ alkylthio, cyano,C₁-C₄ alkyl, C₁-C₄ haloalkyl of 1-3 halo radicals or C₁-C₄ haloalkoxy of1-3 halo radicals; and each R³³ is independently (1) hydrogen radical;(2) C₁-C₄ alkyl radical optionally substituted by a radical ofheterocyclyl, aryl or heteroaryl which is optionally substituted by 1-3radicals of amino, C₁-C₄ alkylamino, di-(C₁-C₄ alkyl)amino, C₁-C₅alkanoylamino, (C₁-C₄ alkoxy)carbonylamino, C₁-C₄ alkylsulfonylamino,hydroxy, C₁-C₄ alkoxy, C₁-C₄ alkylthio, C₁-C₄ alkylsulfinyl, C₁-C₄alkylsulfonyl, cyano, halo, C₁-C₄ alkyl, C₁-C₄ haloalkyl of 1-3 haloradicals or C₁-C₄ haloalkoxy of 1-3 halo radicals; or (3) heterocyclyl,aryl or heteroaryl radical optionally substituted by 1-3 radicals ofamino, C₁-C₄ alkylamino, di-(C₁-C₄ alkyl)amino, C₁-C₅ alkanoylamino,(C₁-C₄ alkoxy)carbonylamino, C₁-C₄ alkylsulfonylamino, hydroxy, C₁-C₄alkoxy, C₁-C₄ alkylthio, C₁-C₄ alkylsulfinyl, C₁-C₄ alkylsulfonyl,cyano, halo, C₁-C₄ alkyl, C₁-C₄ haloalkyl of 1-3 halo radicals or C₁-C₄haloalkoxy of 1-3 halo radicals; and each R³⁴ is independently hydrogenor C₁-C₄ alkyl, aryl, heteroaryl, aryl-C₁-C₄-alkyl orheteroaryl-C₁-C₄-alkyl radical, wherein the aryl and heteroaryl radicalsare optionally substituted by 1-3 radicals of amino, C₁-C₄ alkylamino,di-(C₁-C₄ alkyl)amino, C₁-C₅ alkanoylamino, (C₁-C₄ alkoxy)carbonylamino,C₁-C₄ alkylsulfonylamino, hydroxy, C₁-C₄ alkoxy, C₁-C₄ alkylthio, C₁-C₄alkylsulfinyl, C₁-C₄ alkylsulfonyl, cyano, halo, C₁-C₄ alkyl, C₁-C₄haloalkyl of 1-3 halo radicals or C₁-C₄ haloalkoxy of 1-3 halo radicals;and wherein cycloalkyl is a monocyclic, bicyclic or tricycliccarbocyclic alkyl radical of 3-10 ring members, which is optionallypartially unsaturated or benzo-fused; heterocyclyl is a radical of amonocyclic or bicyclic saturated heterocyclic ring system having 5-8ring members per ring, wherein 1-3 ring members are oxygen, sulfur ornitrogen heteroatoms, which is optionally partially unsaturated orbenzo-fused and optionally substituted by 1-2 oxo or thioxo radicals;aryl is a phenyl, biphenyl or naphthyl radical; and heteroaryl is aradical of a monocyclic or bicyclic aromatic heterocyclic ring systemhaving 5-6 ring members per ring, wherein 1-3 ring members are oxygen,sulfur or nitrogen heteroatoms, which is optionally benzo-fused orsaturated C₃-C₄-carbocyclic-fused.
 3. The compound of claim 2 or apharmaceutically acceptable salt thereof, wherein R¹ is (1) a C₁-C₁₂alkyl, C₂-C₁₂ alkenyl, C₂-C₁₂ alkynyl, cycloalkyl or heterocyclylradical optionally substituted by 1-3 radicals of —OH, —OR³, —SR³,—S(O)R³, —S(O)₂R³, —C(O)R³, —NR³R⁴, aryl, heteroaryl, cycloalkyl orheterocyclyl; or (2) an aryl radical optionally substituted by anoptionally substituted monocyclic heteroaryl or heterocyclyl radical of5-6 ring members which is optionally substituted by a phenyl radical ormonocyclic heteroaryl radical of 5-6 ring members; or (3) a heteroarylradical optionally substituted by an optionally substituted phenyl or amonocyclic heteroaryl or heterocyclyl radical of 5-6 ring members whichis optionally substituted by a phenyl radical or monocyclic heteroarylradical of 5-6 ring members; wherein the phenyl, aryl, heteroaryl,cycloalkyl and heterocyclyl radicals of (1), (2) and (3) are optionallysubstituted by 1-3 radicals of hydroxy, —OR³, —SR³, —S(O)R³, —S(O)₂R³,—C(O)R³, —NR³R⁴, amino, C₁-C₄ alkanoylamino, C₁-C₄ alkylsulfonylamino,C₁-C₄ alkoxycarbonylamino, C₁-C₄ alkoxycarbonyl, cyano, halo, azido,C₁-C₆ alkyl or C₁-C₄ haloalkyl of 1-3 halo radicals; provided that thetotal number of phenyl, aryl, heteroaryl, cycloalkyl and heterocyclylradicals in R¹ is 0-3; wherein each R³ is independently a C₁-C₄ alkyl,C₁-C₄ haloalkyl of 1-3 halo radicals, aryl, heteroaryl, aryl-C₁-C₄-alkylor heteroaryl-C₁-C₄-alkyl radical, wherein the aryl and heteroarylradicals are optionally substituted by 1-3 radicals of hydroxy, C₁-C₄alkoxy, C₁-C₄ alkylthiol, amino, C₁-C₄ alkanoylamino, C₁-C₄alkylsulfonylamino, C₁-C₄ alkylsulfinyl, C₁-C₄ alkylsulfonyl, C₁-C₄alkoxycarbonylamino, C₁-C₄ alkoxycarbonyl, cyano, halo, azido, C₁-C₄alkyl, C₁-C₄ haloalkyl of 1-3 halo radicals or C₁-C₄ haloalkoxy of 1-3halo radicals; and each R⁴ is independently a hydrogen or C₁-C₄ alkylradical; wherein each B is independently a (1) bond; (2) C₁-C₈ alkylradical optionally substituted by (a) a radical of amino, C₁-C₄alkylamino, di-(C₁-C₄ alkyl)amino, C₁-C₅ alkanoylamino, (C₁-C₄alkoxy)carbonylamino, C₁-C₄ alkylsulfonylamino, hydroxy, C₁-C₄ alkoxy,C₁-C₄ alkylthio, cyano, and/or (b) 1-3 halo radicals, and/or (c) 1-2radicals of heterocyclyl, aryl or heteroaryl optionally substituted by1-3 radicals of amino, C₁-C₄ alkylamino, di-(C₁-C₄ alkyl)amino, C₁-C₅alkanoylamino, (C₁-C₄ alkoxy)carbonylamino, C₁-C₄ alkylsulfonylamino,hydroxy, C₁-C₄ alkoxy, C₁-C₄ alkylthio, cyano, halo, C₁-C₄ alkyl, C₁-C₄haloalkyl of 1-3 halo radicals or C₁-C₄ haloalkoxy of 1-3 halo radicals;(3) heterocyclyl radical; or (4) aryl or heteroaryl radical optionallysubstituted by 1-3 radicals of amino, C₁-C₄ alkylamino, di-(C₁-C₄alkyl)amino, C₁-C₅ alkanoylamino, (C₁-C₄ alkoxy)carbonylamino, C₁-C₄alkylsulfonylamino, hydroxy, C₁-C₄ alkoxy, C₁-C₄ alkylthio, cyano, halo,C₁-C₄ alkyl, C₁-C₄ haloalkyl of 1-3 halo radicals or C₁-C₄ haloalkoxy of1-3 halo radicals; wherein each R³⁰ is independently (1) C₁-C₆ alkylradical optionally substituted by 1-3 radicals of —CO₂R³⁴, amino, C₁-C₄alkylamino, di-(C₁-C₄ alkyl)amino, C₁-C₅ alkanoylamino, (C₁-C₄alkoxy)carbonylamino, N-((C₁-C₄ alkoxy)carbonyl)-N-(C₁-C₄ alkyl)amino,aminocarbonylamino, C₁-C₄ alkylsulfonylamino, hydroxy, C₁-C₄ alkoxy,C₁-C₄ alkylthio, C₁-C₄ alkylsulfinyl, C₁-C₄ alkylsulfonyl, cyano, halo,aryl-C₁-C₄-alkoxy, aryl-C₁-C₄-alkylthio, aryl-C₁-C₄-alkylsulfonyl, C₃-C₈cycloalkyl, heterocyclyl, aryl or heteroaryl radicals, wherein thecycloalkyl, heterocyclyl, aryl and heteroaryl radicals are optionallysubstituted by 1-3 radicals of amino, C₁-C₄ alkylamino, di-(C₁-C₄alkyl)amino, C₁-C₅ alkanoylamino, (C₁-C₄ alkoxy)carbonylamino, C₁-C₄alkylsulfonylamino, C₁-C₅ alkanoyl, (C₁-C₄ alkoxy)carbonyl, hydroxy,C₁-C₄ alkoxy, C₁-C₄ alkylthio, C₁-C₄ alkylsulfinyl, C₁-C₄ alkylsulfonyl,cyano, halo, C₁-C₄ alkyl, C₁-C₄ haloalkyl of 1-3 halo radicals or C₁-C₄haloalkoxy of 1-3 halo radicals; (2) heterocyclyl radical optionallysubstituted by 1-3 radicals of amino, C₁-C₄ alkylamino, di-(C₁-C₄alkyl)amino, C₁-C₅ alkanoylamino, (C₁-C₄ alkoxy)carbonylamino, C₁-C₄alkylsulfonylamino, (C₁-C₄ alkoxy)carbonyl, hydroxy, C₁-C₄ alkoxy, C₁-C₄alkylthio, cyano, C₁-C₄ alkyl, C₁-C₄ haloalkyl of 1-3 halo radicals orC₁-C₄ haloalkoxy of 1-3 halo radicals; or (3) aryl or heteroaryl radicaloptionally substituted by 1-3 radicals of amino, C₁-C₄ alkylamino,di-(C₁-C₄ alkyl)amino, C₁-C₅ alkanoylamino, (C₁-C₄ alkoxy)carbonylamino,C₁-C₄ alkylsulfonylamino, (C₁-C₄ alkoxy)carbonyl, hydroxy, C₁-C₄ alkoxy,C₁-C₄ alkylthio, cyano, halo, azido, C₁-C₄ alkyl, C₁-C₄ haloalkyl of 1-3halo radicals or C₁-C₄ haloalkoxy of 1-3 halo radicals; each R³¹ isindependently hydrogen radical or R³⁰; wherein each R³² is independentlyhydrogen or C₁-C₄ alkyl radical; each R³³ is independently hydrogen orC₁-C₄ alkyl radical; and each R³⁴ is independently hydrogen or C₁-C₄alkyl radical.
 4. The compound of claim 3 or a pharmaceuticallyacceptable salt thereof, wherein R¹ is (1) a C₁-C₁₂ alkyl radicaloptionally substituted by 1-3 radicals of —OH, —OR³, —SR³, —S(O)R³,—S(O)₂R³, —C(O)R³, —NR³R⁴, aryl, heteroaryl, cycloalkyl or heterocyclyl;or (2) an aryl radical optionally substituted by an optionallysubstituted monocyclic heteroaryl or heterocyclyl radical of 5-6 ringmembers which is optionally substituted by a phenyl radical ormonocyclic heteroaryl radical of 5-6 ring members; or (3) a heteroarylradical optionally substituted by an optionally substituted phenyl or amonocyclic heteroaryl or heterocyclyl radical of 5-6 ring members whichis optionally substituted by a phenyl radical or monocyclic heteroarylradical of 5-6 ring members; wherein the phenyl, aryl, heteroaryl,cycloalkyl and heterocyclyl radicals of (1), (2) and (3) are optionallysubstituted by 1-3 radicals of hydroxy, —OR³, —SR³, —S(O)R³, —S(O)₂R³,—C(O)R³, —NR³R⁴, amino, acetylamino, methylsulfonylamino, C₁-C₄alkoxycarbonylamino, C₁-C₄ alkoxycarbonyl, cyano, halo, C₁-C₆ alkyl or—CF₃ radicals; provided that the total number of phenyl, aryl,heteroaryl, cycloalkyl and heterocyclyl radicals in R¹ is 0-3; whereineach R³ is independently an C₁-C₄ alkyl, —CF₃, aryl, heteroaryl,aryl-C₁-C₄-alkyl or heteroaryl-C₁-C₄-alkyl radical, wherein the aryl andheteroaryl radicals are optionally substituted by 1-3 radicals ofhydroxy, C₁-C₄ alkoxy, C₁-C₄ alkylthiol, amino, acetylamino,methylsulfonylamino, C₁-C₄ alkylsulfonyl, C₁-C₄ alkoxycarbonylamino,C₁-C₄ alkoxycarbonyl, cyano, halo, C₁-C₄ alkyl, —CF₃ or —OCF₃; and eachR⁴ is independently a hydrogen or methyl radical; wherein each B isindependently a (1) bond; (2) C₁-C₈ alkyl radical optionally substitutedby (a) a radical of amino, C₁-C₄ alkylamino, di-(C₁-C₄ alkyl)amino,C₁-C₅ alkanoylamino, (C₁-C₄ alkoxy)carbonylamino, C₁-C₄alkylsulfonylamino, hydroxy, C₁-C₄ alkoxy, C₁-C₄ alkylthio, cyano,and/or (b) 1-3 halo radicals, and/or (c) 1-2 radicals of heterocyclyl,aryl or heteroaryl optionally substituted by 1-3 radicals of amino,C₁-C₄ alkylamino, di-(C₁-C₄ alkyl)amino, C₁-C₅ alkanoylamino, (C₁-C₄alkoxy)carbonylamino, C₁-C₄ alkylsulfonylamino, hydroxy, C₁-C₄ alkoxy,C₁-C₄ alkylthio, cyano, halo, C₁-C₄ alkyl, —CF₃ or —OCF₃ radicals; (3)heterocyclyl radical; or (4) aryl or heteroaryl radical optionallysubstituted by 1-3 radicals of amino, C₁-C₄ alkylamino, di-(C₁-C₄alkyl)amino, C₁-C₅ alkanoylamino, (C₁-C₄ alkoxy)carbonylamino, C₁-C₄alkylsulfonylamino, hydroxy, C₁-C₄ alkoxy, C₁-C₄ alkylthio, cyano, halo,C₁-C₄ alkyl, —CF₃ or —OCF₃ radicals; each A is independently a (1)hydrogen radical; (2) halo, cyano or nitro radical; (3) —C(O)—R³⁰,—C(O)—OR³¹, —C(O)—NR³²R³¹ or —C(NR³²)—NR³²R³¹ radical; (4) —OR³¹,—O—C(O)—R³¹ or —O—C(O)—NR³²R³¹ radical; (5) —SR³¹, —S(O)—R³⁰, —S(O)₂—R³⁰or —S(O)₂—NR³²R³¹ radical; or (6) —NR³²R³¹, —NR³³—C(O)—R³¹,—NR³³—C(O)—OR³⁰, —NR³³—C(O)—NR³²R³¹, —NR³³—C(NR³²)—NR³²R³¹,—NR³³—S(O)₂—R³⁰ or —NR³³—S(O)₂—NR³²R³¹ radical; wherein each R³⁰ isindependently (1) C₁-C₆ alkyl radical optionally substituted by 1-3radicals of —CO₂R³⁴, amino, C₁-C₄ alkylamino, di-(C₁-C₄ alkyl)amino,C₁-C₅ alkanoylamino, (C₁-C₄ alkoxy)carbonylamino, N-((C₁-C₄alkoxy)carbonyl)-N-(C₁-C₄ alkyl)amino, aminocarbonylamino, C₁-C₄alkylsulfonylamino, hydroxy, C₁-C₄ alkoxy, C₁-C₄ alkylthio, C₁-C₄alkylsulfinyl, C₁-C₄ alkylsulfonyl, cyano, halo, aryl-C₁-C₄-alkoxy,aryl-C₁-C₄-alkylthio, aryl-C₁-C₄-alkylsulfonyl, C₃-C₈ cycloalkyl,heterocyclyl, aryl or heteroaryl radicals, wherein the cycloalkyl,heterocyclyl, aryl and heteroaryl radicals are optionally substituted by1-3 radicals of amino, C₁-C₄ alkylamino, di-(C₁-C₄ alkyl)amino, C₁-C₅alkanoylamino, (C₁-C₄ alkoxy)carbonylamino, C₁-C₄ alkylsulfonylamino,C₁-C₅ alkanoyl, (C₁-C₄ alkoxy)carbonyl, hydroxy, C₁-C₄ alkoxy, C₁-C₄alkylthio, C₁-C₄ alkylsulfinyl, C₁-C₄ alkylsulfonyl, cyano, halo, C₁-C₄alkyl, —CF₃ or —OCF₃ radicals; (2) heterocyclyl radical optionallysubstituted by 1-3 radicals of amino, C₁-C₄ alkylamino, di-(C₁-C₄alkyl)amino, C₁-C₅ alkanoylamino, (C₁-C₄ alkoxy)carbonylamino, C₁-C₄alkylsulfonylamino, (C₁-C₄ alkoxy)carbonyl, hydroxy, C₁-C₄ alkoxy, C₁-C₄alkylthio, cyano, C₁-C₄ alkyl, C₁-C₂ haloalkyl of 1-3 halo radicals or—OCF₃; or (3) aryl or heteroaryl radical optionally substituted by 1-3radicals of amino, C₁-C₄ alkylamino, di-(C₁-C₄ alkyl)amino, C₁-C₅alkanoylamino, (C₁-C₄ alkoxy)carbonylamino, C₁-C₄ alkylsulfonylamino,(C₁-C₄ alkoxy)carbonyl, hydroxy, C₁-C₄ alkoxy, C₁-C₄ alkylthio, cyano,halo, C₁-C₄ alkyl, —CF₃ or —OCF₃ radicals; each R³¹ is independentlyhydrogen radical or R³⁰; and each R³³ is independently a hydrogen ormethyl radical.
 5. The compound of claim 4 or a pharmaceuticallyacceptable salt thereof, wherein R is a —C(O)—R³¹ or —S(O)₂—R³⁰ radical;provided that the combined total number of aryl, heteroaryl, cycloalkyland heterocyclyl radicals in R⁹, R¹⁰ and R¹¹ is 0-2.
 6. The compound ofclaim 5 or a pharmaceutically acceptable salt thereof, wherein R¹ is (1)an C₁-C₁₂ alkyl radical optionally substituted by 1-3 radicals of —OH,—OR³, —SR³, —S(O)₂R³, —NR³R⁴, aryl, heteroaryl, cycloalkyl orheterocyclyl; or (2) an aryl radical optionally substituted by anoptionally substituted monocyclic heteroaryl or heterocyclyl radical of5-6 ring members which is optionally substituted by a phenyl radical ormonocyclic heteroaryl radical of 5-6 ring members; or (3) a heteroarylradical optionally substituted by an optionally substituted phenyl or amonocyclic heteroaryl or heterocyclyl radical of 5-6 ring members whichis optionally substituted by a phenyl radical or monocyclic heteroarylradical of 5-6 ring members; wherein the phenyl, aryl, heteroaryl,cycloalkyl and heterocyclyl radicals of (1), (2) and (3) are optionallysubstituted by 1-3 radicals of hydroxy, —OR³, —SR³, —S(O)₂R³, —NR³R⁴,amino, acetylamino, methylsulfonylamino, C₁-C₄ alkoxycarbonylamino,C₁-C₄ alkoxycarbonyl, cyano, halo, C₁-C₆ alkyl or —CF₃ radicals;provided that the total number of phenyl, aryl, heteroaryl, cycloalkyland heterocyclyl radicals in R¹ is 0-2; wherein each R³ is independentlya C₁-C₄ alkyl, —CF₃, aryl, heteroaryl, aryl-C₁-C₂-alkyl orheteroaryl-C₁-C₂-alkyl radical, wherein the aryl and heteroaryl radicalsare optionally substituted by 1-2 radicals of hydroxy, C₁-C₄ alkoxy,C₁-C₄ alkylthiol, amino, acetylamino, methylsulfonylamino, C₁-C₄alkylsulfonyl, C₁-C₄ alkoxycarbonylamino, C₁-C₄ alkoxycarbonyl, cyano,halo, C₁-C₄ alkyl, —CF₃ or —OCF₃; wherein each B is independently a (1)bond; (2) C₁-C₄ alkyl radical optionally substituted by (a) a radical ofamino, C₁-C₂ alkylamino, di-(C₁-C₂ alkyl)amino, C₁-C₂ alkanoylamino,(C₁-C₄ alkoxy)carbonylamino, hydroxy, C₁-C₂ alkoxy, and/or (b) 1-2 haloradicals, and/or (c) a radical of heterocyclyl, aryl or heteroaryloptionally substituted by 1-2 radicals of amino, C₁-C₂ alkylamino,di-(C₁-C₂ alkyl)amino, C₁-C₂ alkanoylamino, (C₁-C₄ alkoxy)carbonylamino,C₁-C₂ alkylsulfonylamino, hydroxy, C₁-C₂ alkoxy, C₁-C₂ alkylthio, halo,C₁-C₄ alkyl, —CF₃ or —OCF₃ radicals; (3) heterocyclyl radical; or (4)aryl or heteroaryl radical optionally substituted by 1-2 radicals ofamino, C₁-C₂ alkylamino, di-(C₁-C₂ alkyl)amino, C₁-C₂ alkanoylamino,(C₁-C₄ alkoxy)carbonylamino, C₁-C₂ alkylsulfonylamino, hydroxy, C₁-C₂alkoxy, C₁-C₂ alkylthio, halo, C₁-C₄ alkyl, —CF₃ or —OCF₃ radicals; eachA is independently a (1) hydrogen radical; (2) halo radical; (3)—C(O)—R³⁰, —C(O)—OR³¹, —C(O)—NR³²R³¹ or —C(NR³²)—NR³²R³¹ radical; (4)—OR³¹ radical; (5) —SR³¹, —S(O)₂—R³⁰ or —S(O)₂—NR³²R³¹ radical; or (6)—NR³²R³¹, —NR³³—C(O)—R³¹, —NR³³—C(O)—OR³⁰, —NR³³—C(O)—NR³²R³¹,—NR³³—S(O)₂—R³⁰ or —NR³³—S(O)₂—NR³²R³¹ radical; wherein each R³⁰ isindependently (1) —CF₃ or C₁-C₄ alkyl radical optionally substituted by1-2 radicals of —CO₂R³⁴, amino, C₁-C₂ alkylamino, di-(C₁-C₂ alkyl)amino,C₁-C₂ alkanoylamino, (C₁-C₄ alkoxy)carbonylamino, N-((C₁-C₄alkoxy)carbonyl)-N-(C₁-C₄ alkyl)amino, hydroxy, C₁-C₄ alkoxy, oraryl-C₁-C₂-alkoxy, heterocyclyl, aryl or heteroaryl radicals, whereinthe heterocyclyl, aryl and heteroaryl radicals are optionallysubstituted by 1-3 radicals of amino, C₁-C₂ alkylamino, di-(C₁-C₂alkyl)amino, C₁-C₂ alkanoylamino, (C₁-C₄ alkoxy)carbonylamino, C₁-C₅alkanoyl, (C₁-C₄ alkoxy)carbonyl, hydroxy, C₁-C₄ alkoxy, halo, C₁-C₄alkyl, —CF₃ or —OCF₃ radicals; (2) heterocyclyl radical optionallysubstituted by 1-2 radicals of (C₁-C₄ alkoxy)carbonyl, hydroxy or C₁-C₄alkyl; or (3) aryl or heteroaryl radicals optionally substituted by 1-2radicals of amino, C₁-C₂ alkylamino, di-(C₁-C₂ alkyl)amino, C₁-C₂alkanoylamino, hydroxy, C₁-C₂ alkoxy, halo, C₁-C₄ alkyl, —CF₃ or —OCF₃radicals; each R³¹ is independently hydrogen radical or R³⁰; and whereincycloalkyl is a monocyclic carbocyclic alkyl radical of 3-6 ringmembers, which is optionally partially unsaturated or benzo-fused; andheterocyclyl is a radical of a monocyclic saturated heterocyclic ringsystem having 5-8 ring members per ring, wherein 1-3 ring members areoxygen, sulfur or nitrogen heteroatoms, which is optionally partiallyunsaturated or benzo-fused and optionally substituted by 1-2 oxo orthioxo radicals.
 7. The compound of claim 6 or a pharmaceuticallyacceptable salt thereof, wherein R¹ is (1) an C₁-C₄ alkyl radicalsubstituted by 1-2 radicals of —OH, —OR³, —NR³R⁴, aryl or heteroaryl; or(2) an aryl radical optionally substituted by a monocyclic heteroarylradical of 5-6 ring members; or (3) a heteroaryl radical optionallysubstituted by a phenyl radical; wherein the phenyl, aryl and heteroarylradicals of (1), (2) and (3) are optionally substituted by 1-2 radicalsof hydroxy, —OR³, —SR³, —S(O)₂R³, —NR³R⁴, amino, acetylamino,methylsulfonylamino, C₁-C₄ alkoxycarbonylamino, C₁-C₄ alkoxycarbonyl,halo, C₁-C₆ alkyl or —CF₃ radicals; provided that the total number ofphenyl, aryl and heteroaryl radicals in R¹ is 0-2; wherein each R³ isindependently a C₁-C₄ alkyl, —CF₃, aryl, heteroaryl, aryl-C₁-C₂-alkyl orheteroaryl-C₁-C₂-alkyl radical, wherein the aryl and heteroaryl radicalsare optionally substituted by 1-2 radicals of hydroxy, C₁-C₂ alkoxy,C₁-C₂ alkylthiol, amino, acetylamino, methylsulfonylamino, C₁-C₂alkylsulfonyl, C₁-C₄ alkoxycarbonylamino, C₁-C₄ alkoxycarbonyl, halo,C₁-C₂ alkyl, —CF₃ or —OCF₃; wherein each B is independently a (1) bond;(2) C₁-C₄ alkyl radical; or (3) aryl or heteroaryl radical optionallysubstituted by a radical of amino, C₁-C₂ alkylamino, di-(C₁-C₂alkyl)amino, C₁-C₂ alkanoylamino, (C₁-C₄ alkoxy)carbonylamino, C₁-C₂alkylsulfonylamino, hydroxy, C₁-C₂ alkoxy, C₁-C₂ alkylthio, halo, C₁-C₄alkyl, —CF₃ or —OCF₃ radicals; each A is independently a (1) hydrogenradical; (2) halo radical; (3) —C(O)—R³⁰, —C(O)—NR³²R³¹ or—C(NR³²)—NR³²R³¹ radical; (4) —OR³¹ radical; (5) —SR³¹, —S(O)₂—R³⁰ or—S(O)₂—NR³²R³¹ radical; or (6) —NR³²R³¹, —NR³³—C(O)—R³¹ or—NR³³S(O)₂—R³⁰ radical; wherein each R³⁰ is independently (1)heterocyclyl radical optionally substituted by 1-2 radicals of (C₁-C₄alkoxy)carbonyl, hydroxy or C₁-C₄ alkyl; or (2) heteroaryl radicalsoptionally substituted by 1-2 radicals of amino, C₁-C₂ alkylamino,di-(C₁-C₂ alkyl)amino, C₁-C₂ alkanoylamino, hydroxy, C₁-C₂ alkoxy, halo,C₁-C₄ alkyl, —CF₃ or —OCF₃ radicals; and each R³¹ is independentlyhydrogen radical or (1) —CF₃ or C₁-C₄ alkyl radical optionallysubstituted by 1-2 radicals of hydroxy, C₁-C₂ alkoxy oraryl-C₁-C₂-alkoxy, aryl or heteroaryl radicals, wherein the aryl andheteroaryl radicals are optionally substituted by 1-2 radicals of amino,C₁-C₂ alkylamino, di-(C₁-C₂ alkyl)amino, C₁-C₂ alkanoylamino, (C₁-C₄alkoxy)carbonylamino, C₁-C₅ alkanoyl, (C₁-C₄ alkoxy)carbonyl, hydroxy,C₁-C₄ alkoxy, halo, C₁-C₄ alkyl, —CF₃ or —OCF₃ radicals; or (2) aryl orheteroaryl radical optionally substituted by 1-2 radicals of amino,C₁-C₂ alkylamino, di-(C₁-C₂ alkyl)amino, C₁-C₂ alkanoylamino, hydroxy,C₁-C₂ alkoxy, halo, C₁-C₄ alkyl, —CF₃ or —OCF₃ radicals.
 8. The compoundof claim 7 or a pharmaceutically acceptable salt thereof, wherein R¹ isaryl or heteroaryl radicals optionally substituted by 1-2 radicals ofhydroxy, —OR³, —SR³, —S(O)₂R³, —NR³R⁴, amino, acetylamino,methylsulfonylamino, C₁-C₄ alkoxycarbonylamino, C₁-C₄ alkoxycarbonyl,halo, C₁-C₆ alkyl or —CF₃ radicals; provided that the total number ofaryl and heteroaryl radicals in R¹ is 1-2; wherein each R³ isindependently a C₁-C₄ alkyl, —CF₃, aryl, heteroaryl, arylmethyl orheteroarylmethyl radical; wherein each B is independently a (1) bond;(2) C₁-C₄ alkyl radical; or (3) aryl or heteroaryl radical; each A isindependently a (1) hydrogen radical; (2) halo radical; or (3) —C(O)—R³⁰or —C(O)—NR³²R³¹ radical; wherein each R³⁰ is independently aheterocyclyl radical optionally substituted by C₁-C₄ alkyl; each R³¹ isindependently hydrogen radical or (1) —CF₃ or C₁-C₄ alkyl radicaloptionally substituted by 1-2 radicals of aryl or heteroaryl radicals;or (2) aryl or heteroaryl radical; and wherein each R³² is independentlya hydrogen or methyl radical.
 9. The compound of claim 8 or apharmaceutically acceptable salt thereof, wherein R¹ is an aryl radicaloptionally substituted by 1-2 radicals of hydroxy, —OR³, —S(O)₂R³,—NR³R⁴, amino, acetylamino, methylsulfonylamino, halo, C₁-C₄ alkyl or—CF₃ radicals; provided that the total number of aryl and heteroarylradicals in R¹ is 1-2; R⁵, R⁶, R⁹ and R¹⁰ are each a hydrogen radical;or CR⁵-CR⁶ is C═C; and wherein heterocyclyl is a radical ofpyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiamorpholinyl,4-benzyl-piperazin-1-yl, pyrimidinyl, tetrahydrofuryl, pyrazolidonyl,pyrazolinyl, pyridazinonyl, pyrrolidonyl, tetrahydrothienyl or itssulfoxide or sulfone derivative, 2,3-dihydroindolyl,tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl,1,2,3,4-tetrahydro-1-oxo-isoquinolinyl, 2,3-dihydrobenzofuryl,benzopyranyl, methylenedioxyphenyl or ethylenedioxyphenyl; aryl is aphenyl, biphenyl or naphthyl radical; and heteroaryl is a radical ofimidazolyl, pyrrolyl, pyrazolyl, pyridyl, pyrazinyl, triazolyl, furyl,thienyl, oxazolyl, thiazolyl, indolyl, quinolinyl, isoquinolinyl,5,6,7,8-tetrahydroquinolyl, 5,6,7,8-tetrahydroisoquinolinyl,quinoxalinyl, benzothiazolyl, β-carbolinyl, benzofuryl, benzimidazolylor benzoxazolyl.
 10. The compound of claim 9 or a pharmaceuticallyacceptable salt thereof, wherein R¹ is a phenyl or biphenyl radicaloptionally substituted by 1-2 radicals of hydroxy, —OR³, —S(O)₂R³,—NR³R⁴, amino, acetylamino, methylsulfonylamino, halo, C₁-C₄ alkyl or—CF₃ radicals; provided that the total number of aryl and heteroarylradicals in R¹ is 1-2; wherein each R³ is independently an C₁-C₄ alkyl,—CF₃, phenyl, heteroaryl, phenylmethyl or heteroarylmethyl radical; andwherein heterocyclyl is a radical of pyrrolidinyl, piperidinyl,piperazinyl, morpholinyl, thiamorpholinyl, 4-benzyl-piperazin-1-yl orpyrimidinyl; and heteroaryl is a radical of imidazolyl, pyrrolyl,pyrazolyl, pyridyl, pyrazinyl, indolyl, quinolinyl, isoquinolinyl,benzothiazolyl, benzofuryl, benzimidazolyl or benzoxazolyl.
 11. Thecompound of claim 10 or a pharmaceutically acceptable salt thereof,wherein R¹ is a phenyl or biphenyl radical optionally substituted by 1-2radicals of hydroxy, —OR³, halo, methyl or —CF₃ radicals; provided thatthe total number of aryl and heteroaryl radicals in R¹ is 1-2; andwherein each R³ is independently an methyl, —CF₃, phenyl, heteroaryl,phenylmethyl or heteroarylmethyl radical.
 12. A pharmaceuticalcomposition comprising a compound of claim 1 and a pharmaceuticallyacceptable carrier.